JP6463229B2 - Method for producing polyalkylene glycol derivative having amino group at terminal, polymerization initiator used therefor, and alcohol compound as raw material thereof - Google Patents

Description

  The present invention relates to a method for producing a polyalkylene glycol derivative having an amino group at a terminal, a polymerization initiator used therefor, and an alcohol compound as a raw material thereof.

  In recent years, in the field of drug delivery systems, a method of encapsulating a drug in a polymer micelle using a block copolymer formed from a hydrophilic segment and a hydrophobic segment has been proposed (for example, Patent Documents 1 to 3). See). By using this method, the polymer micelle functions as a drug carrier, and various effects including release of the drug in vivo and intensive administration to a lesion site are obtained.

  Many examples using a polyalkylene glycol skeleton have been proposed as hydrophilic segments (see, for example, Patent Documents 1 to 3). A compound having a polyalkylene glycol skeleton has low toxicity in vivo and can delay excretion in the kidney. As a result, the residence time in blood can be extended as compared with a compound having no polyalkylene glycol skeleton. Therefore, when using a polyalkylene glycol derivative as a micelle, the dose and the number of administrations can be reduced.

  Among polyalkylene glycol derivatives, a compound having an amino group at the terminal is derived into a block copolymer composed of a polyalkylene glycol skeleton and an amino acid skeleton by a ring-opening polymerization reaction with α-amino acid-N-carboxyanhydride. It is possible. And many examples which enclose a chemical | medical agent in a polymer micelle using the obtained block copolymer are proposed (for example, refer patent documents 1-3).

  A method for synthesizing such a polyalkylene glycol derivative having an amino group at the terminal is also known (see, for example, Patent Documents 4 and 5). In these methods, after the polymerization of alkylene oxide using a metal salt of a monohydric alcohol as a polymerization initiator, the polymerization terminal is converted to a hydroxyl group and then to a 2-cyanoethoxy group, and the final reduction is achieved through hydrogen reduction of the cyano group. To an amino group-containing substituent (3-amino-1-propoxy group).

  As another method for synthesizing a polyalkylene glycol derivative having an amino group, for example, a method of polymerizing with ethylene oxide using a polymerization initiator in which the amino group is protected with silyl, and then deriving to an amino group by deprotection (non-patent) However, this method has a problem in that the terminal is limited to a 2-amino-1-ethoxy group. Moreover, the reactivity is low, and it has been a subject to have a long time of 96 hours to increase the molecular weight to 6000 (see Non-Patent Document 1).

Japanese Patent No. 2690276 Japanese Patent No. 2777530 JP 11-335267 A Japanese Patent No. 3050228 Japanese Patent No. 3562000 Japanese Patent No. 4581248

Bioconj. Chem. 1992, 3, 275-276.

  As disclosed in Patent Document 4, it is difficult to completely dissolve a metal salt of a monohydric alcohol used as a polymerization initiator in a polymerization solvent (for example, an organic solvent such as tetrahydrofuran (hereinafter abbreviated as THF)). In many cases, in order to dissolve the metal salt in the polymerization solvent, it is necessary to leave an excessive amount of alcohol as an initiator raw material during the synthesis of the metal salt (for example, in Patent Document 4, a polymerization initiator is used). 13 mol of methanol for 2 mol of certain sodium methoxide). However, when these alcohols are present in the reaction system, a decrease in polymerization rate is unavoidable, and severe reaction conditions such as high temperature and high pressure are required to increase the polymerization rate. Further, since the inside of the system does not become uniform unless the polymerization initiator is dissolved in the polymerization solvent, there is a problem that the polymerization proceeds only from the dissolved polymerization initiator and the degree of dispersion of the resulting polyalkylene glycol derivative is widened.

  Moreover, monohydric alcohol often contains a trace amount of water. When a polymerization initiator is prepared in a state containing water and polymerized with alkylene oxide, a polymer compound having hydroxyl groups at both ends (hereinafter abbreviated as diol polymer) is by-produced. When the boiling point of the monohydric alcohol is sufficiently higher than that of water, the amount of water can be reduced by dehydrating under reduced pressure. For example, methanol used when the terminal is a methyl group has a lower boiling point than that of water. The water cannot be removed by dehydration underneath. Therefore, when a metal salt is prepared using methanol and alkylene oxide is polymerized, formation of a diol polymer is inevitable. Diol polymers are very difficult to separate and purify because their physical properties such as structure and molecular weight are similar to the target. When the previous reaction is carried out with the diol polymer contained as an impurity, a polymer containing amino groups at both ends is formed unless appropriate reaction conditions are selected. If a polymer containing such impurities is used as it is, there is a possibility that the intended performance may not be obtained due to the design of the polymer micelle agent. Therefore, when performing the polymerization reaction, the moisture must be kept as low as possible.

  In the synthesis methods described in Patent Document 4 and Patent Document 5, a cyano group is converted to an aminomethyl group by hydrogen reduction using a Raney nickel catalyst. In this method, depending on the use of the polyalkylene glycol derivative, there is a possibility that a trace amount of metal may be mixed in the final product. Furthermore, this reaction generally requires a high temperature, and as a result, β-elimination of acrylonitrile proceeds and the target product cannot be obtained in good yield, or by an amine addition reaction to imine, which is an intermediate of nitrile reduction. There also remained problems such as the risk of secondary secondary and tertiary amine formation and polyacrylonitrile by-product.

  As a method of synthesizing a polyalkylene glycol derivative having an amino group at the terminal without using a heavy metal, a method of polymerizing with an alkylene oxide using an alkoxide protected with an amino group as a polymerization initiator can be considered. For example, when a silyl group is used as a protecting group for an amino group, since a silicon-nitrogen bond is weaker than a silicon-oxygen bond, it is very difficult to selectively synthesize an alcohol in which only an amino group is silylated. No examples have been reported.

  An object of the present invention is to solve the above-mentioned problems in the prior art, and to provide a method for producing a polyalkylene glycol derivative having an amino group at a terminal with narrow dispersion and high purity, and a polymerization initiator used in the method. And

  As a result of intensive studies to achieve the above object, the present inventors have used a compound having sufficient solubility in a polymerization solvent in which an amino group is protected by a protective group as a polymerization initiator. It is possible to control the polymerization of alkylene oxide and diol polymer formation under the conditions, and to remove the diol polymer when it is formed, and to prevent heavy metal contamination and by-product formation. The present invention has been completed by finding that it can be derived into a highly pure and narrowly dispersed polyalkylene glycol having an amino group at the terminal.

（一般式（Ｉ）中、Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３の炭素原子及びヘテロ原子の総数が４以上であり、Ｍはアルカリ金属を表す） That is, the present invention uses a compound represented by the following general formula (I) as a polymerization initiator, and includes at least a step of reacting the polymerization initiator with an alkylene oxide. The present invention relates to a method for producing a derivative.

(In the general formula (I), R _A ^1a and R _A ^1b each independently represent an amino group protecting group, or one of them represents a hydrogen atom and the other represents an amino group protecting group, or R _A ^1a And R _A ^1b represents a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbon atoms, or branched or cyclic having 3 to 6 carbon atoms And R _A ³ is a single bond, a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent group having 3 to 20 carbon atoms. Wherein the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a heteroatom, the carbon atoms of R _A ² and R _A ³ and The total number of heteroatoms is 4 or more, and M represents an alkali metal)

（一般式（Ｉ）〜（ＩＩＩ）中、
Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３の炭素原子及びヘテロ原子の総数が４以上であり、Ｒ_Ａ ^４は水素原子、或いは置換されていてもよい直鎖状、分岐状又は環状の炭素数１〜１２の炭化水素基であり、かつ該炭化水素基はヘテロ原子を含んでいてもよく、Ｒ_Ａ ^５は炭素数２〜８のアルキレン基であり、Ｍはアルカリ金属を表し、ｎは１〜４５０の整数である）
工程ａ）前記一般式（Ｉ）で表される重合開始剤とアルキレンオキシドとを重合溶媒中で反応させることにより、下記一般式（Ｉ−１）で表される化合物を得る工程

（一般式（Ｉ−１）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＲ_Ａ ^５は前記一般式（ＩＩ）及び（ＩＩＩ）について定義したとおりであって、前記一般式（ＩＩ）及び（ＩＩＩ）のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＲ_Ａ ^５と同一であり、Ｍはアルカリ金属を表し、前記一般式（Ｉ）のＭと同一であり、ｒは１〜４４５の整数を表す）；
工程ｂ）前記一般式（Ｉ−１）で表される化合物と下記一般式（Ｉ−２）で表される化合物とを反応させることにより、前記一般式（ＩＩ）で表される化合物を得る工程

（一般式（Ｉ−２）中、Ｒ_Ａ ^４及びＲ_Ａ ^５は前記一般式（ＩＩ）及び（ＩＩＩ）について定義したとおりであって、前記一般式（ＩＩ）及び（ＩＩＩ）のＲ_Ａ ^４及びＲ_Ａ ^５と同一であり、ｋは０〜５の整数を表し、Ｌは脱離基を表す）；及び
工程ｃ）前記一般式（ＩＩ）で表される化合物を脱保護し、前記一般式（ＩＩＩ）で表される化合物を得る工程。 According to another aspect, the present invention relates to a method for producing a polyalkylene glycol derivative having an amino group at a terminal, including steps a) to c).

(In the general formulas (I) to (III),
R _A ^1a and R _A ^1b each independently represent an amino protecting group, one represents a hydrogen atom, the other represents an amino protecting group, or R _A ^1a and R _A ^1b are bonded to each other. A cyclic protecting group which forms a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbon atoms, or a branched or cyclic divalent hydrocarbon group having 3 to 6 carbon atoms. R _A ³ is a single bond or a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent hydrocarbon group having 3 to 20 carbon atoms, And the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a hetero atom, the total number of carbon atoms and hetero atoms of R _A ² and R _A ³ is 4 or more. There, R _A ⁴ is a hydrogen atom, or optionally substituted linear, branched or A Jo hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group may contain a hetero atom, R _A ⁵ is an alkylene group having 2 to 8 carbon atoms, M represents an alkali metal , N is an integer from 1 to 450)
Step a) A step of obtaining a compound represented by the following general formula (I-1) by reacting a polymerization initiator represented by the general formula (I) with an alkylene oxide in a polymerization solvent.

(In the general formula (I-1), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ are as defined for the general formulas (II) and (III), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ^{5 in the} general formulas (II) and (III) are the same, M represents an alkali metal, and M in the general formula (I) And r represents an integer of 1 to 445);
Step b) A compound represented by the general formula (II) is obtained by reacting a compound represented by the general formula (I-1) with a compound represented by the following general formula (I-2). Process

(In the general formula (I-2), R _A ⁴ and R _A ⁵ are as defined for the general formulas (II) and (III), and R _A ^{4 in the} general formulas (II) and (III)). And R _A ⁵ , k represents an integer of 0 to 5, L represents a leaving group); and step c) the compound represented by the general formula (II) is deprotected, A step of obtaining a compound represented by the formula (III).

（一般式（ｉ）中、Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３の炭素原子及びヘテロ原子の総数が４以上である） According to another aspect, the present invention relates to a protected amino group-containing alcohol compound represented by the following general formula (i).

(In General Formula (i), R _A ^1a and R _A ^1b each independently represent an amino group protecting group, one represents a hydrogen atom, the other represents an amino group protecting group, or R _A ^1a And R _A ^1b represents a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbon atoms, or branched or cyclic having 3 to 6 carbon atoms And R _A ³ is a single bond, a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent group having 3 to 20 carbon atoms. Wherein the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a heteroatom, the carbon atoms of R _A ² and R _A ³ and The total number of heteroatoms is 4 or more)

（一般式（Ｉ）中、Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３の炭素原子及びヘテロ原子の総数が４以上であり、Ｍはアルカリ金属を表す） According to still another aspect, the present invention relates to a metal salt of a protected amino group-containing alcohol compound represented by the following general formula (I).

(In the general formula (I), R _A ^1a and R _A ^1b each independently represent an amino group protecting group, or one of them represents a hydrogen atom and the other represents an amino group protecting group, or R _A ^1a And R _A ^1b represents a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbon atoms, or branched or cyclic having 3 to 6 carbon atoms And R _A ³ is a single bond, a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent group having 3 to 20 carbon atoms. Wherein the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a heteroatom, the carbon atoms of R _A ² and R _A ³ and The total number of heteroatoms is 4 or more, and M represents an alkali metal)

  By using the method for producing a polyalkylene glycol derivative having an amino group at the terminal according to the present invention, it becomes possible to perform polymerization without substantial presence of a polymerization initiator raw material alcohol that causes a decrease in the polymerization rate. The alkylene oxide can be polymerized under mild conditions. In addition, the generation of impurities such as diol polymer due to a small amount of moisture can be suppressed, and even if moisture is mixed and polymer impurities are generated, they can be removed by separation and purification. An alkylene glycol derivative can be produced. In addition, when this method also includes a purification step, the polyalkylene glycol derivative can be produced on an industrial scale because lyophilization is not required when the polyalkylene glycol derivative is purified and taken out. It has the further advantage that simplification can be realized. In addition, by using a polymerization initiator with a protected amino group, it is possible to avoid the use of a reduction method using heavy metals and to prevent contamination of by-products associated therewith. The risk of product contamination can be reduced. Further, the polyalkylene glycol derivative produced by the production method according to the present invention is narrowly dispersible because the polymerization initiator is uniformly dissolved in the system, and has a hydrophilic segment useful in the field of drug delivery systems. It can be used very advantageously in deriving into block copolymers formed from hydrophobic segments. Furthermore, since the amino group-protected alcohol compound and the alkali metal salt thereof according to the present invention can be used as a more useful alternative polymerization initiator and precursor in the production method of polyalkylene glycol derivatives. Very useful.

[Embodiment 1]
The present invention uses a compound represented by the following general formula (I) as a polymerization initiator, and includes at least a step of reacting the polymerization initiator with an alkylene oxide. It is a manufacturing method. According to one embodiment, the present invention is characterized by sequentially performing the following steps a) to c). (Hereinafter, this embodiment may be referred to as “Embodiment 1”.)
Step a) A step of reacting a polymerization initiator represented by the general formula (I) with an alkylene oxide in a polymerization solvent to obtain a compound represented by the following general formula (I-1),
Step b) reacting a compound represented by the general formula (I-1) with a compound represented by the following general formula (I-2) to obtain a compound represented by the following general formula (II); c) A step of deprotecting the compound represented by the general formula (II) to obtain a compound represented by the general formula (III).

In the general formulas (I), (I-1), and (II), R _A ^1a and R _A ^1b each independently represent an amino group protecting group, or one represents a hydrogen atom and the other represents an amino group. R _A ^1a and R _A ^1b represent a cyclic protecting group that is bonded to each other to form a ring with the nitrogen atom of the amino group. The protecting group is preferably a protecting group that can be deprotected without using a heavy metal catalyst. The types of protecting groups represented by R _A ^1a and / or R _A ^1b can be exemplified by, for example, the following (a) to (e), but are not limited thereto.

(A) Protecting group having a structure represented by Si (R ¹ ) ₃ (trialkylsilyl group)
When R _A ^1a and R _A ^{1b in the} general formulas (I), (I-1), and (II) each independently represent an amino group-protecting group, and one is a hydrogen atom and the other is an amino group R _A ^1a and / or R _A ^1b may be a protective group (trialkylsilyl group) having a structure represented by Si (R ¹ ) ₃ .
In the structure represented by the above Si (R ¹ ) ₃ , R ¹ is independently a linear chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon group having 3 to 6 carbon atoms. is there. Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring together with the silicon atom to which they are bonded. Specific examples of R ¹ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, and cyclopropyl group. , Cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. In addition, when R ¹ is bonded to each other to form a ring with a silicon atom, a group in which one hydrogen atom is eliminated from these groups can be mentioned.
Preferable specific examples of the protective group having a structure represented by Si (R ¹ ) ₃ include, but are not limited to, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, and the like.

( _A ) Protecting group having a structure represented by R _A ⁶ OCO In the above general formulas (I), (I-1), and (II), R _A ^1a and R _A ^1b are each independently an amino group protecting group. , And when one represents a hydrogen atom and the other represents an amino-protecting group, R _A ^1a and / or R _A ^1b may be a protecting group having a structure represented by R _A ⁶ OCO.
In the structure represented by the above R _A ⁶ OCO, R _A ⁶ is a monovalent hydrocarbon residue having 1 to 20 carbon atoms, and the residue is a halogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, It may contain a silicon atom, a phosphorus atom or a boron atom.
Examples of the protecting group represented by the structure of R _A ⁶ OCO include methyloxycarbonyl group, ethyloxycarbonyl group, isobutyloxycarbonyl group, tert-butyloxycarbonyl group, tert-amyloxycarbonyl group, 2,2,2-trichloro Ethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, phenylethyloxycarbonyl group, 1- (1-adamantyl) -1-methylethyloxycarbonyl group, 1,1-dimethyl-2-haloethyloxycarbonyl group, 1 , 1-dimethyl-2,2-dibromoethyloxycarbonyl group, 1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl group, 1-methyl-1- (4-biphenylyl) ethyloxycarbonyl group, 1- (3,5-di-t-butylphenyl)- 1-methylethyloxycarbonyl group, 2- (2′-pyridyl) ethyloxycarbonyl group, 2- (4′-pyridyl) ethyloxycarbonyl group, 2- (N, N-dicyclohexylcarboxamido) ethyloxycarbonyl group, 1-adamantyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, 1-isopropylallyloxycarbonyl group, cinnamyloxycarbonyl group, 4-nitrocinnamyloxycarbonyl group, 8-quinolyloxycarbonyl group, N- Hydroxypiperidinyloxycarbonyl group, alkyldithiocarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-bromobenzyloxycarbonyl group, p-chlorobenzene Jyloxycarbonyl group, 2,4-dichlorobenzyloxycarbonyl group, 4-methylsulfinylbenzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, diphenylmethyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, 9 -(2,7-dibromo) fluorenylmethyloxycarbonyl group, 2,7-di-t-butyl- [9- (10,10-dioxo-thioxanthyl)] methyloxycarbonyl group, 4-methoxyphenacyloxy Carbonyl group, 2-methylthioethyloxycarbonyl group, 2-methylsulfonylethyloxycarbonyl group, 2- (p-toluenesulfonyl) ethyloxycarbonyl group, [2- (1,3-dithianyl)] methyloxycarbonyl group, 4 -Methylthiophenyloxycarbonyl 2,4-dimethylthiophenyloxycarbonyl group, 2-phosphonioethyloxycarbonyl group, 2-triphenylphosphonioisopropyloxycarbonyl group, 1,1-dimethyl-2-cyanoethyloxycarbonyl group, m-chloro-p -Acyloxybenzyloxycarbonyl group, p- (dihydroxyboryl) benzyloxycarbonyl group, 5-benzisoxazolylmethyloxycarbonyl group, 2- (trifluoromethyl) -6-chromonylmethyloxycarbonyl group, phenyloxy Carbonyl group, m-nitrophenyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group and phenyl (o-nitrophenyl) Examples thereof include, but are not limited to, methyloxycarbonyl group. Of these, tert-butyloxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group, allyloxycarbonyl group, benzyloxycarbonyl group, and 9-fluorenylmethyloxycarbonyl group are preferable.

(C) When the cyclic protecting groups R _A ^1a and R _A ^1b are bonded to each other to form a ring together with the nitrogen atom of the amino group, such cyclic protecting groups include an N-phthaloyl group, N -Tetrachlorophthaloyl group, N-4-nitrophthaloyl group, N-dithiasucciloyl group, N-2,3-diphenylmaleoyl group, N-2,5-dimethylpyrrolyl group, N-2, 5-bis (triisopropylsiloxy) pyrrolyl group, N-1,1,3,3-tetramethyl-1,3-disilaisoindoyl group, 3,5-dinitro-4-pyridonyl group, 1,3,5 -A dioxazinyl group, 2,2,5,5-tetramethyl-2,5-disila-1-azacyclopentane and the like can be exemplified, but are not limited thereto. Of these, an N-phthaloyl group is preferable.

(D) Other protecting groups When R _A ^1a and / or R _A ^1b is a protecting group other than (a) to (c) above, examples of such protecting groups include a benzyl group and a p-methoxybenzyl group. P-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, (2-trimethylsilyl) ethanesulfonyl group, allyl group, pivaloyl group, methoxymethyl group, di (4-methoxyphenyl) methyl group, 5-dibenzosuberyl group, trinylmethyl Group, (4-methoxyphenyl) diphenylmethyl group, 9-phenylfluorenyl group, [2- (trimethylsilyl) ethoxy] methyl group, N-3-acetoxypropyl group and the like, but are limited to these protecting groups. Not done. Preferably, a protecting group that can be deprotected without using a heavy metal catalyst can be appropriately selected and used. Of these, a benzyl group, a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, and an allyl group are preferable.

In the general formulas (I), (I-1), (II), and (III), R _A ² is a straight chain having 1 to 6 carbon atoms, or a branched or cyclic structure having 3 to 6 carbon atoms. It is a divalent hydrocarbon group. Specific examples of R _A ² include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, Examples include a group in which one hydrogen atom is eliminated from each of a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

In the general formulas (I), (I-1), (II), and (III), R _A ³ may contain a single bond or a hetero atom such as a nitrogen atom, an oxygen atom, or a sulfur atom. It is a C1-C20 linear or C3-C20 branched or cyclic divalent hydrocarbon group. Specific examples of R _A ³ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, octyl group. Decyl group, dodecyl group, phenyl group, 0-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, 2,6- Examples include a group in which one hydrogen atom is eliminated from each of a xylyl group, a 3,4-xylyl group, a 3,5-xylyl group, a mesityl group, and the like. In these hydrocarbon groups, a part of carbon atoms may be substituted with a hetero atom such as a nitrogen atom, an oxygen atom, or a sulfur atom (however, in the general formula (I), oxygen constituting O ⁻ M ⁺ In general formulas (I-1), (II), and (III), the bond with the atom is excluded from the bond with the oxygen atom constituting (OR _A ⁵ ). Among _them, it is preferred that _R ^{A 3} is a structure represented by the following general formula (VII). This is because in step a), the compatibility between the polymerization initiator represented by the above general formula (I) and the polymerization solvent is improved.
-(OR _A ⁵ ) _P- (VII)
In the general formula _{(VII), R} ^{A 5} is the general formula (I-1), (I -2), the same as _R ^{A 5} in (II), and (III), specific examples thereof As described later. p is an integer of 1 to 10, and is preferably an integer of 1 to 5, more preferably an integer of 1 to 2, from the viewpoint of purifying the alcohol compound that is a raw material of the polymerization initiator by distillation.

Here, the total number of carbon atoms of R _A ² and R _A ³ is 4 or more. In the case where some of the carbon atoms are replaced by a heteroatom in R _A ^3, the total number was also calculated as the number of carbon atoms of the hetero atom may be at least 4. The total number of carbon atoms of R _A ² and R _A ³ is preferably 4-15, more preferably 4-9. In the polymerization initiator represented by the general formula (I), nitrogen atoms and oxygen atoms at both ends ^- chain of R _A ² and R _A ³ connecting the (O oxygen atoms constituting the M ⁺⁾ In the compound represented by the general formula (I), there is a possibility that a protecting group on nitrogen may be transferred onto oxygen by increasing the chain length of the polymer to 4 or more. Metastases can be prevented in the substrate.

In the general formulas (I-2), (II), and (III), R _A ⁴ represents a hydrogen atom or a linear, branched, or cyclic carbon atom having 1 to 12 carbon atoms that may be substituted. It is a hydrogen group, and the hydrocarbon group may contain a hetero atom. Specific examples of R _A ⁴ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexyl group, and an octyl group. Decyl group, dodecyl group, phenyl group, 0-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, 2,6- Examples include xylyl group, 3,4-xylyl group, 3,5-xylyl group, mesityl group, vinyl group, allyl group and the like. When R _A ⁴ has a substituent, examples of the substituent include an acetalized formyl group, a cyano group, a formyl group, a carboxyl group, an amino group, an alkoxycarbonyl group having 1 to 6 carbon atoms, and 2 to 7 carbon atoms. An acylamide group, the same or different tri (C1-6 alkyl) siloxy group, siloxy group, silylamino group, maleimide group, thiol group, hydroxyl group, methacryloyloxy group, acryloyloxy group, active ester group, and azide group Can be mentioned. Specific examples of R _A ⁴ having a substituent include, but are not limited to, those represented by the following structural formula. In addition, the following formula shows the terminal portion of R _A ⁴ having a substituted structure, and the dotted line in the formula indicates that the hydrocarbon portion of R _A ⁴ can take variations as exemplified above. The number of substituents is not particularly limited, but is preferably 1 to 3. Such substituents may be further protected with any appropriate protecting group.

In the general formulas (I-1), (I-2), (II), and (III), R _A ⁵ is an alkylene group having 2 to 8 carbon atoms. Among these, an alkylene group having 2 to 3 carbon atoms is preferable. That is, R _A ⁵ is preferably an ethylene group or a propylene group. In the above general formulas (I-1), (I-2), (II), and (III), as the (OR _A ⁵ ) unit, one kind of oxyalkylene group such as an oxyethylene group or oxypropylene is used. It may be comprised only by group, and 2 or more types of oxyalkylene groups may be mixed. When two or more kinds of oxyalkylene groups are mixed, (OR _A ⁵ ) may be one obtained by randomly polymerizing two or more different oxyalkylene groups, or may be one obtained by block polymerization.

  In the general formulas (I) and (I-1), M represents an alkali metal. Specific examples of M include lithium, sodium, potassium, cesium, sodium-potassium alloy and the like.

  In said general formula (I-1), r represents the integer of 1-445, for example, Preferably it is an integer of 10-395, More preferably, it is an integer of 20-345.

  In the general formula (I-2), k is an integer of 0 to 5, for example. When k is 0, the compound represented by the general formula (I-2) has a low boiling point and may be difficult to handle or may be highly toxic. Therefore, k is preferably an integer of 1 to 5, Furthermore, it is more preferable that it is an integer of 1-3.

  In the general formula (I-2), L represents a leaving group. Specific examples of L include Cl, Br, I, trifluoromethanesulfonate (hereinafter referred to as TfO), p-toluenesulfonate (hereinafter referred to as TsO), methanesulfonate (hereinafter referred to as MsO), and the like. However, it is not limited to these.

  In the general formulas (II) and (III), n represents an integer of 1 to 450, preferably an integer of 10 to 400, and more preferably an integer of 20 to 350. n is also represented by the sum of r and k described above.

In selecting each compound represented by the general formulas (I), (I-1), (I-2), and (II) used in each step of the production method of Embodiment 1, a desired final product In general formulas (I), (I-1), (I-2), and (II), the desired R _A ^1a can be obtained so that a compound represented by general formula (III) can be obtained. , R _A ^1b , R _A ² , R _A ³ , R _A ⁴ , R _A ⁵ , M, r, k, L, and n can be selected.

  Moreover, this Embodiment 1 has the pre-process for synthesize | combining the compound represented by general formula (I) used as a polymerization initiator as an optional process before process a) -c). You may do it. This pre-process uses the process (pre-process 1) which synthesize | combines the compound represented by the following general formula (i) used as a precursor of a polymerization initiator, and the compound represented by general formula (i). It includes a step of synthesizing the compound represented by the general formula (I) used as a polymerization initiator (pre-step 2). In addition, this embodiment includes a mode in which the previous step 2 is continued from the previous step 1 and a mode in which only the previous step 2 is performed without going through the previous step 1 as the previous step. The scheme of the previous step 2 is shown below.

（上記一般式（ｉ）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＭは、上記一般式（Ｉ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＭと同一である。）

(In the general formula (i), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and M are R _A ^1a , R _A ^1b , R _A ² , R in the general formula (I). It is the same as _A ³ and M.)

  Moreover, this Embodiment 1 has the post-processing process which refine | purifies the compound represented by general formula (III) obtained by process c) as an optional process after process a) -c). It may be.

  In the description of the following embodiment, the description will be given in the order of the pre-process 1-2, the steps a) -c), and the post-processing step in time series.

[Pre-process 1]
The pre-process 1 is a process of synthesizing the alcohol compound represented by the general formula (i) used as a precursor of the polymerization initiator, and the production thereof can be performed, for example, in the following process (i-1). Yes, but not limited to this.

（上記一般式（ｉａ）及び（ｉｂ）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、及びＲ_Ａ ^３は上記一般式（ｉ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、及びＲ_Ａ ^３と同一である。すなわち、上記一般式（Ｉ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、及びＲ_Ａ ^３と同一である。Ｌ^１は脱離基を表す。）

(In the general formulas (ia) and (ib), R _A ^1a , R _A ^1b , R _A ² , and R _A ³ represent R _A ^1a , R _A ^1b , R _A ² , And R _A ^3. That is, R ¹ is the same as R _A ^1a , R _A ^1b , R _A ² and R _A ^{3 in the} general formula (I), and L ¹ represents a leaving group.

In the general formulas (ia) and (ib), specific examples of the leaving group for L ¹ include, but are not limited to, Cl, Br, I, TfO, TsO, MsO and the like.

  When synthesizing the compound represented by the general formula (i) by carrying out the step (i-1), for example, a basic compound is added to the compound represented by the general formula (ia) without a solvent. Then, the compound represented by the general formula (ib) may be dropped and mixed to react, or the compound represented by the general formula (ia) is dissolved in an appropriate solvent and then the basic is reacted. You may make it react by adding a compound and then dripping and mixing the compound represented by general formula (ib). The amount of the compound represented by the general formula (ib) is, for example, 1 to 5 times, preferably 1.5 to 3 times the number of moles of the compound represented by the general formula (ia). From the viewpoint of selectively reacting the protective group only with the amino group, the amount of 1.5 to 2 times is more preferable.

  When a solvent is used in the above step (i-1), specific examples of the solvent include ethers such as THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, and methylene chloride. Examples include, but are not limited to, halogens, N, N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, acetone and the like. Although the usage-amount of a solvent is not specifically limited, It is 1-20 times amount with respect to the mass of the compound represented by general formula (ia), Preferably it is 2-10 times amount, More preferably, it is 2-5 times Amount.

  Specific examples of the basic compound used in the step (i-1) include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, and carbonates such as sodium carbonate, potassium carbonate and cesium carbonate. Metal alkoxides such as salts, sodium methoxide, sodium ethoxide, potassium t-butoxide, metal hydrides such as sodium hydride and potassium hydride, primary, secondary and tertiary aliphatic amines , Mixed amines, aromatic amines, heterocyclic amines, aqueous ammonia and the like, but are not limited thereto. The amount of the basic compound used is, for example, 1 to 5 times, preferably 1.5 to 3 times, more preferably 1.5 to 2 times the number of moles of the compound represented by the general formula (ia). Double the amount.

  Although the reaction temperature in the said process (i-1) can be performed within the range of melting | fusing point-boiling point of the solvent to be used, it is -60 degreeC-150 degreeC, for example, Preferably it is 0 degreeC-80 degreeC. The completion of the reaction in the step (i-1) can be performed when the compound represented by the general formula (ia) disappears by gas chromatography or when the general formula (i) is obtained as a main product. .

If R _A ^1a and R _A ^1b are desired to be different protecting groups, or if the protecting group has a high steric hindrance and the protecting group is simultaneously applied not only to the amino group but also to the hydroxy group, the amino group Is protected with a first protecting group, then the hydroxy group is protected with another deprotectable protecting group, the amino group is subsequently protected with a second protecting group, and finally the hydroxy group is deprotected. And can be synthesized. Depending on the reaction conditions, selectivity between the amino group and the hydroxy group may not be obtained, and the hydroxy group may be protected, or only one protective group may be introduced into the amino group. The compound represented by general formula (i) and other by-products can be separated by precision distillation. Moreover, it is preferable to refine | purify the compound represented by general formula (i) by distillation, and to remove a water | moisture content, even when a by-product does not produce | generate. In this case, the water content of the compound represented by the general formula (i) is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less.

When the compound represented by the general formula (i) contains a hetero atom in R _A ³ , as another method for producing the compound represented by the general formula (i), for example, next to the hetero atom of R _A ³ Although the method like the following process (i-2)-(i-3) using the compound represented by general formula (if) which has a hydrogen atom is mentioned, it is not limited to this.

（上記一般式（ｉｃ）、（ｉｄ）、（ｉｅ）、及び（ｉｆ）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＬ^１は上記一般式（ｉａ）及び（ｉｂ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＬ^１と同一である。Ｌ^２は脱離基を表す。）

(In the general formulas (ic), (id), (ie), and (if), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and L ¹ are represented by the general formulas (ia) and (It is the same as R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and L ^{1 in} ib), and L ² represents a leaving group.)

In the general formulas (ic) and (ie), specific examples of the leaving group for L ² include, but are not limited to, Cl, Br, I, TfO, TsO, MsO and the like.

  When carrying out the step (i-2), for example, a basic compound is added to the compound represented by the general formula (ic) without a solvent, and then the compound represented by the general formula (id) is dropped. In addition, the compound represented by the general formula (ic) may be dissolved in an appropriate solvent, and then the basic compound is added, and then the compound represented by the general formula (id). You may make it react by dripping and mixing. The amount of the compound represented by the general formula (id) is, for example, 2 to 10 times, preferably 2 to 5 times, more preferably, the number of moles of the compound represented by the general formula (ic). Is 2-3 times the amount.

  When a solvent is used in the step (i-2), specific examples of the solvent are the same as the specific examples of the solvent described in the step (i-1). Although the usage-amount of a solvent is not specifically limited, It is 1-20 times amount with respect to the mass of the compound represented by general formula (ic), Preferably it is 2-10 times amount, More preferably, it is 2-5 times amount. It is.

  Specific examples of the basic compound used in the step (i-2) are the same as the specific examples of the basic compound described in the step (i-1). The amount of the basic compound used is, for example, 2 to 10 times, preferably 2 to 5 times, more preferably 2 to 3 times the number of moles of the compound represented by the general formula (ic). .

  Although the reaction temperature in the said process (i-2) can be performed within the range of melting | fusing point-boiling point of the solvent to be used, it is -60 degreeC-150 degreeC, for example, Preferably it is 0 degreeC-80 degreeC. The reaction can be completed when the compound represented by the general formula (ic) disappears by gas chromatography or when the compound represented by the general formula (ie) is obtained as a main product.

Next, when the step (i-3) is carried out to synthesize the compound represented by the general formula (i), the general formula (if) is added to the reaction solution after the completion of the step (i-2). The compound represented by general formula (if) may be added directly, or once the compound represented by general formula (ie) is purified and taken out, then the compound represented by general formula (if) and the base It may be added dropwise to a mixed solution of an organic compound and a solvent. Moreover, the process of (i-3) can also be performed without a solvent. The amount of the compound represented by the general formula (if) is 1 to 30 times, preferably 2 to 20 times, more preferably 5 with respect to the number of moles of the compound represented by the general formula (ie). -10 times the amount. For example, when R _A ³ is a compound represented by the above general formula (VII), the compound represented by the general formula (if) is a diol, but the compound represented by the general formula (if) is represented by the general formula By using an excess amount with respect to the number of moles of the compound represented by (ie), one terminal hydroxy group of the compound represented by the general formula (if) can be reacted.

  When a solvent is used in the step (i-3), specific examples of the solvent are the same as the specific examples of the solvent described in the step (i-1). Although the usage-amount of a solvent is not specifically limited, It is 1-20 times amount with respect to the mass of the compound represented by general formula (ie), Preferably it is 2-10 times amount, More preferably, it is 2-5 times amount. It is. Specific examples of the basic compound used in the step (i-3) are the same as the specific examples of the basic compound described in the step (i-1). The amount of the basic compound used is, for example, 1 to 2 times, preferably 1 to 1.5 times, and more preferably 1 to 1.2 times the number of moles of the compound represented by the general formula (ie). Double the amount.

Although the reaction temperature in the said process (i-3) can be performed within the range of melting | fusing point-boiling point of the solvent to be used, it is -60 degreeC-150 degreeC, for example, Preferably it is 0 degreeC-80 degreeC. The reaction can be completed at the time when the compound represented by the general formula (ie) disappears by gas chromatography. Depending on the reaction conditions, both the heteroatom on R _A ³ and the terminal hydroxy group may react with the compound represented by the general formula (ie) to produce a by-product. The compound represented by (i) and the by-product can be separated. Moreover, it is preferable to refine | purify the compound represented by general formula (i) by distillation, and to remove a water | moisture content, even when a by-product does not produce | generate. In this case, the water content of the compound represented by the general formula (i) is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less.

[Pre-process 2]
The previous step 2 is a step of obtaining the compound represented by the general formula (I) by reacting the compound represented by the general formula (i) with an alkali metal or an alkali metal compound.

In the previous step 2, the alkali metal or alkali metal compound to be reacted with the compound represented by the general formula (i) is an alkali metal represented by M, an alkali metal hydride represented by M ⁺ H ⁻ , R An organic alkali metal represented by _X ⁻ M ⁺ , [R _Y ] ^{· −} M ⁺ (R _X represents an optionally substituted alkyl group having 1 to 20 carbon atoms, preferably 1 carbon atom) represents an 20 alkyl group or an arylalkyl group having 7 to 20 carbon atoms of, R _Y represents an even aromatic compound has a substituent), and R _Z O ^- M ⁺ monovalent represented A substance selected from the group consisting of alkali metal salts of alcohol (R _Z represents an alkyl group having 1 to 6 carbon atoms) shall be used.

Specific examples of the M alkali metal include lithium, sodium, potassium, cesium, sodium-potassium alloy and the like. Specific examples of M ⁺ H ⁻ include sodium hydride and potassium hydride. R _X ^- M Specific examples of ^+, ethyllithium, sodium ethyl, n- butyl lithium, sec- butyl lithium, tert- butyl lithium, 1,1-diphenyl hexyl lithium, 1,1-diphenyl-3-methylpentyl Examples include lithium, 1,1-diphenylmethyl potassium, cumyl sodium, cumyl potassium, cumyl cesium and the like. Specific examples of [R _Y ] ^{· −} M ⁺ include lithium naphthalenide, sodium naphthalenide, potassium naphthalenide, anthracene lithium, anthracene sodium, anthracene potassium, biphenyl sodium, sodium 2-phenylnaphthalenide, Phenanthrene sodium, sodium acenaphthylene, sodium benzophenone ketyl, sodium 1-methylnaphthalenide, potassium 1-methylnaphthalenide, sodium 1-methoxynaphthalenide, potassium 1-methoxynaphthalenide These compounds can be used singly or in combination of two or more. R _Z O ^- Examples of _{R Z} in M ^+, methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, sec- butyl group, tert- butyl group, n- pentyl group, isopentyl Group, n-hexyl group and the like, but are not limited thereto. Of these, sodium, potassium, sodium hydride and potassium hydride are preferable from the viewpoint of suppressing side reactions as the alkali metal or alkali metal compound, and sodium naphthalenide and potassium naphtha are preferable from the viewpoint of high reactivity. Renide, sodium anthracene, anthracene potassium, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide are preferred.

  The amount of alkali metal or alkali metal compound used in the reaction of the preceding step 2 is 0.5 to 3.0 equivalents, preferably 0. 0 to the number of moles of the compound represented by the general formula (i). 8 to 2.0 equivalents, more preferably 0.9 to 1.0 equivalents. In particular, when an alkali metal compound that can also function as a polymerization initiator is used in step a), the amount used must be 1.0 equivalent or less. For example, when potassium methoxide is used, it is necessary to prevent the potassium methoxide from acting as a polymerization initiator in step a) by distilling off the methanol produced in the previous step 2 under reduced pressure after the synthesis of the polymerization initiator. There is.

  In the previous step 2, when the compound represented by the general formula (I) is synthesized, for example, the compound represented by the general formula (i) purified by distillation in the previous step 1 is dissolved in an appropriate solvent. The alkali metal or the alkali metal compound may be added directly, or the compound represented by the general formula (i) may be added when the alkali metal or the alkali metal compound is dissolved in an appropriate solvent. Specific examples of the solvent used in the preceding step 2 include ethers such as THF and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene, but are not limited thereto. . When using a solvent, it is preferable to use what was distilled using dehydrating agents, such as metallic sodium. The water content of the solvent is, for example, 50 ppm or less, preferably 10 ppm or less, more preferably 5 ppm or less. Although the usage-amount of a solvent is not specifically limited, It is 1-50 times amount with respect to the mass of the compound represented by the said general formula (i), Preferably it is 2-10 times amount, More preferably, it is 2-5 times amount. It is. The reaction in the previous step 2 is carried out at a temperature of −78 to 100 ° C., preferably 0 ° C. to the reflux temperature of the solvent used (for example, 0 ° C. to 66 ° C. which is the reflux temperature of THF). The system can be cooled and heated.

  Among them, as the solvent used in the previous step 2, it is preferable to use the same solvent as the solvent used as the polymerization solvent in the step a) described later. This is because whether or not the polymerization initiator synthesized in the previous step 2 is dissolved in the polymerization solvent used in the step a) can be confirmed in advance during the synthesis of the polymerization initiator in the previous step 2. Specifically, for example, THF is used as the reaction solvent in the previous step 2, and potassium hydride is used as the alkali metal compound (for example, 1.0 equivalent or less of potassium hydride with respect to the compound represented by the general formula (i)). When THF is used as the polymerization solvent in step a), the solubility of the polymerization initiator in the polymerization solvent can be confirmed as follows. The reaction in the previous step 2 proceeds to reduce the powdered potassium hydride and generate hydrogen. When the polymerization initiator represented by the above general formula (I) produced at this time does not precipitate in THF, which is the reaction solvent of the previous step 2, and finally all of the potassium hydride has reacted, the reaction solution By confirming whether there is any salt precipitation or cloudiness, the solubility of the polymerization initiator in the polymerization solvent in the subsequent step a) can be confirmed in advance.

  Moreover, although the following method can be illustrated as another method which confirms beforehand the solubility of the polymerization initiator represented by general formula (I) in the polymerization solvent used in step a), it is not limited thereto. As described above, the compound represented by the general formula (i) is reacted with an alkali metal or an alkali metal compound to synthesize a polymerization initiator represented by the general formula (I), and then represented by the general formula (I). Solvents and reagents other than the polymerization initiator are removed by a conventional method, and the polymerization initiator represented by the general formula (I) is taken out. The obtained polymerization initiator represented by the general formula (I) is dissolved in, for example, a polymerization solvent used in the subsequent step a) at a concentration of 20 wt%, and whether salt precipitation or white turbidity is visually observed. Can be confirmed.

As described above, when a polymerization initiator is prepared in a state where the monohydric alcohol that is a raw material of the polymerization initiator contains moisture, and polymerization is performed with alkylene oxide using the polymerization initiator, a diol polymer is formed as a by-product. To do. The diol polymer is extremely difficult to separate from the target product, and if the diol polymer or a polymer containing impurities derived from the diol polymer is used as it is, there is a high possibility that the intended performance of the polymer micelle agent cannot be obtained. Therefore, when performing the polymerization reaction in the subsequent step a), it is preferable to keep the water content of the reaction system containing the compound (polymerization initiator) represented by the general formula (I) as low as possible. In this regard, the compound represented by the general formula (i), which is a precursor of the compound represented by the general formula (I), is, for example, R _A ^1a = R _A ^1b = triethylsilyl group, R _A ² = CH _{In the case of 2} CH ₂ CH ₂ , R _A ³ = OCH ₂ CH ₂ , the boiling point is as high as 120 ° C. (10 Pa), and there is a sufficient difference in boiling point from water, so water can be separated by drying under reduced pressure. Is possible. Therefore, before the reaction of the compound represented by the general formula (i) and the alkali metal or the alkali metal compound in the previous step 2, the compound represented by the general formula (i) is sufficiently dried under reduced pressure. It is preferable to carry out the distillation after a short time. The water content of the compound represented by the general formula (i) after distillation is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less. As described above, when the polymerization initiator is used to perform a polymerization reaction by making the compound represented by the general formula (i), which is a raw material of the polymerization initiator, into a state containing as little water as possible, a diol polymer is used. Can be better suppressed.

  In addition, from the amount of the raw material alcohol represented by the general formula (i) used in the previous step 2 and the total weight of the reaction solution after the previous step 2, the reaction solution after the completion of the previous step 2 (polymerization start) The concentration (mmol / g) of a substance that can act as a polymerization initiator in the reaction solution after the synthesis of the agent can be determined. That is, the concentration of the substance that can act as a polymerization initiator in the reaction solution after the end of the previous step 2 is “the amount of the raw material alcohol (i) used (mmol) / the weight of the entire reaction solution after the end of the previous step 2”. (G) ". This is because when the raw material alcohol represented by the general formula (i) remains in the reaction solution after completion of the previous step 2, the raw material alcohol also functions as a polymerization initiator. Since the reaction in the (next step a) is an equilibrium reaction, the polymer terminal alkoxide produced by the reaction of the compound represented by the general formula (I) as a polymerization initiator draws the proton of the raw material alcohol (i), and the alkoxide (polymerization). Act as an initiator). However, as will be described later, it is desirable that the amount of raw material alcohol remaining in the reaction solution after completion of the previous step 2 is as small as possible. The reaction solution after completion of the previous step 2 can be used as it is as a polymerization initiator solution in the subsequent step a).

Conventionally, a sodium salt or potassium salt, which is a polymerization initiator that is generally used, often does not dissolve alone in a polymerization solvent such as THF. In that case, in order to perform uniform polymerization, it is necessary to leave an excessive amount of alcohol as an initiator raw material (for example, in Patent Document 4, 13 mol of methanol with respect to 2 mol of sodium methoxide as a polymerization initiator). However, when these alcohols are present in the reaction system, a decrease in polymerization rate is unavoidable, and severe reaction conditions such as high temperature and high pressure are required to increase the polymerization rate. In contrast, the alcohol derivative in which the amino group represented by the general formula (I) used as a polymerization initiator in the present embodiment is protected with a protecting group has a structure similar to the polymerization solvent in the structure of the molecule, It is easily soluble in the polymerization solvent. For example, when R _A ³ has an oxyethylene structure, the compound represented by the general formula (I) is readily soluble in ether compounds including THF, diethylene glycol dimethyl ether and the like. Therefore, it is not necessary to leave the initiator raw material alcohol in order to dissolve the polymerization initiator in the polymerization solvent. Therefore, the polymerization rate is improved and the polymerization can be performed under mild conditions.

  Thus, in order to obtain a sufficient reaction rate under the mild conditions in the next step a), it is preferable to synthesize a polymerization initiator with a small residual amount of initiator raw material alcohol in the previous step 2. Specifically, after synthesizing the polymerization initiator represented by the general formula (I) from the initiator raw material alcohol represented by the general formula (i), the polymerization initiator represented by the general formula (I) The mass ratio of the initiator raw material alcohol represented by the general formula (i) is preferably 100: 0 to 80:20 (mol%), more preferably 100: 0 to 90:10 (mol%). React so that For that purpose, in the previous step 2, the number of moles of alkali metal or alkali metal compound used is 0.8 to 1.5, preferably 0.9 to 1.0, of the compound represented by formula (i). It is preferable to carry out under such conditions.

  Moreover, after synthesizing the polymerization initiator represented by the above general formula (I), the initiator raw material alcohol represented by the general formula (i) can be distilled off from the reaction system under reduced pressure. In that case, the mass ratio of the polymerization initiator represented by the general formula (I) and the initiator raw material alcohol represented by the general formula (i) after the end of the previous step 2 is 100: 0 to 98: 2 (mol). %), It is preferable to remove the raw alcohol until it becomes 100% to 99: 1 (mol%), more preferably the raw alcohol is removed. By reducing the raw material alcohol remaining amount, the polymerization rate in the next step a) can be further increased.

In this embodiment, as described above, the initiator raw material alcohol compound represented by the general formula (i), which is a factor for improving the solubility of the polymerization initiator in the polymerization solvent, and also a factor for decreasing the polymerization rate, is not left. In both cases, the compound represented by the general formula (I) as an initiator can be dissolved in a polymerization solvent. The structure that plays the role is R _A ³ in the general formula (I). For example, when the polymerization solvent is THF, R _A ³ is preferably represented by the structure represented by the general formula (VII) ((OR _A ⁵ ) By setting _p ), the compatibility between the polymerization initiator and the polymerization solvent is increased, and the polymerization initiator can be dissolved in the polymerization solvent without substantial presence of the initiator raw material alcohol. As a result, polymerization in a uniform system becomes possible, and a narrowly dispersed polyalkylene glycol derivative can be synthesized under mild conditions.

[Step a)]
Step a) is a step of reacting the compound represented by the above general formula (I) (polymerization initiator) with an alkylene oxide in a polymerization solvent. According to step a), a compound represented by the following general formula (I-1) can be obtained.

In step a), the compound represented by general formula (I) is preferably completely dissolved in the polymerization solvent and then reacted with the alkylene oxide. As described above, the compound represented by the general formula (I) is easily soluble in the polymerization solvent even when the compound represented by the general formula (i), which is the starting alcohol, is substantially absent. Among these, from the viewpoint of high compatibility with the polymerization solvent, R _A ³ in the general formula (I) is an alkylene oxide structure (— (OR _A ⁵ ) _P —) represented by the above general formula (VII). It is preferable to have. The fact that the compound represented by the general formula (I) can be completely dissolved in the polymerization solvent can be confirmed by, for example, visual observation of no salt precipitation or cloudiness in the polymerization solvent. At this time, it is desirable that salt precipitation or cloudiness is not observed in a state where the mass of the polymerization solvent relative to the mass of the compound represented by the general formula (I) is 10 times or less (and 1 time or more). That is, the concentration of the compound represented by the general formula (I) in the polymerization solvent solution containing the compound represented by the general formula (I) is 9.1% by weight or more (and 50% by weight or less). It is desirable that salt precipitation and cloudiness are not observed. After confirming that the compound represented by the general formula (I) can be completely dissolved in the polymerization solvent as described above, the polymerization including the compound represented by the general formula (I) with the concentration at the time of confirmation. A solvent solution may be used for the polymerization reaction, or may be further used for the polymerization reaction in a diluted state by adding a polymerization solvent. The amount of the polymerization solvent may be adjusted so as to be, for example, 1 to 50 times, preferably 2 to 25 times the mass of the alkylene oxide used at the start of the polymerization reaction.

  Further, as described above, since the presence of the raw material alcohol causes a decrease in the polymerization rate, it is preferable to use the polymerization initiator in a state where the raw material alcohol is small in step a). For example, when the preceding step 2 is carried out before the step a), it is represented by the general formula (I) at a substance amount ratio obtained in the preceding step 2, preferably 100: 0 to 80:20. It is preferable to use a reaction product (a reaction product with less raw material alcohol) containing a polymerization initiator and a raw material alcohol represented by the general formula (i) as it is dissolved in a polymerization solvent.

  As the polymerization solvent used in step a), a cyclic ether compound having 4 to 10 carbon atoms or a linear or branched ether compound is preferably used from the viewpoint of high compatibility with the polymerization initiator. Specific examples of the cyclic ether compound include furan, 2,3-dihydrofuran, 2,5-dihydrofuran, 2,3-dimethylfuran, 2,5-dimethylfuran, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 3 -Methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 1,2-methylenedioxybenzene, 1,3-dioxolane, 2-methyl-1,3-dioxolane, 4-methyl-1,3-dioxolane, 2,2- Dimethyl-1,3-dioxolane, 3,4-dihydro-2H-pyran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, 2,4-dimethyl-1,3-dioxane, 1,4-benzo Although dioxane, 1,3,5-trioxane, oxepane, etc. can be illustrated, it is not limited to these. Specific examples of the linear or branched ether compound include monoethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether, but are not limited thereto. In particular, THF is preferably used. Moreover, it is also possible to use polymerization solvents other than an ether compound, and specific examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, but are not limited thereto. The polymerization solvent to be used may be a single solvent or a combination of two or more. The combination of compounds and the mixing ratio in the case of combination are not limited.

  The amount of the polymerization solvent used for the polymerization reaction is not particularly limited, but is, for example, 1 to 50 times, preferably 2 to 30 times, and more preferably 3 to 20 times the mass of the alkylene oxide to be used. . As the polymerization solvent, for example, a solvent distilled using a dehydrating agent such as metallic sodium is preferably used. The water content of the polymerization solvent is, for example, 50 ppm or less, preferably 10 ppm or less, more preferably 5 ppm or less.

  Specific examples of the alkylene oxide used include ethylene oxide and propylene oxide. Of these, ethylene oxide is preferable because of its high polymerizability. The amount ratio of the compound represented by the general formula (I) used in the polymerization reaction and the alkylene oxide is not particularly limited, but the substance amount ratio of the compound represented by the general formula (I): alkylene oxide is: For example, 1: 1 to 1: 450, preferably 1:10 to 1: 400.

  In step a), for example, alkylene oxide may be added all at once or sequentially to a reaction system in which the compound represented by formula (I) is dissolved in a polymerization solvent. Alternatively, a solution obtained by dissolving alkylene oxide in the above-described polymerization solvent may be dropped into the above reaction system. The polymerization can be performed, for example, at a temperature of 30 to 80 ° C., preferably 50 to 80 ° C., more preferably 60 to 80 ° C. The pressure during the polymerization reaction is, for example, 1.0 MPa or less, preferably 0.5 MPa or less. The degree of progress of the polymerization reaction can be monitored by GPC, and the end point can be the point at which the change in the conversion rate of the alkylene oxide ceases. As described above, this embodiment is advantageous in that it does not require severe reaction conditions such as high temperature and high pressure during polymerization.

[Step b)]
Step b) is a step of reacting the compound represented by the general formula (I-1) obtained in step a) with the compound represented by the following general formula (I-2). By the step b), a compound represented by the following general formula (II) can be obtained.
R _A ⁴ (OR _A ⁵ ) _k L (I-2)

In step b), when synthesizing the compound represented by the general formula (II), for example, in the reaction solution (reaction solution containing (I-1)) after completion of the reaction in step a) The compound represented by the formula (I-2) may be added directly, or the compound represented by the general formula (I-2) may be dissolved in an appropriate solvent as necessary. Specific examples of the solvent to be used include ethers such as THF and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene. Although the usage-amount of a solvent is not specifically limited, It is 1-50 times amount with respect to the mass of the compound represented by the said general formula (I-2), Preferably it is 2-10 times amount, More preferably, it is 2-5. Double the amount. The reaction can be carried out at a temperature of 0 to 100 ° C., preferably 40 to 70 ° C. The reaction system is cooled or heated as necessary. The amount of the compound represented by the general formula (I-2) to be used is, for example, 1 to 50 equivalents, preferably 1 to 40 equivalents, relative to the number of moles of the compound represented by the general formula (I-1). More preferably, it is 1-30 equivalent. The degree of progress of the reaction can be monitored by ¹ H-NMR, and the end point can be the time when the peak derived from the hydroxyl group generated when the reaction solution is quenched with water.

  The reaction of step b) proceeds without a catalyst, but can be accelerated by using a base catalyst. Base catalysts include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, sodium methoxide, sodium ethoxide and potassium t-butoxide. Metal alkoxides, metal hydrides such as sodium hydride, potassium hydride, primary, secondary, tertiary aliphatic amines, hybrid amines, aromatic amines, heterocyclic amines Ammonia water or the like can be used, but is not limited thereto. The amount of the base catalyst used is, for example, 0.1 to 30 times, preferably 1 to 20 times the number of moles of the compound represented by the above general formula (I-1).

  In step b), an alkali adsorbent is used to separate the alkali metal salt produced by the reaction between the compound represented by general formula (I-1) and the compound represented by general formula (I-2). May be further used. Suitable alkali adsorbents include aluminum hydroxide (for example, “Kyoward 200” manufactured by Kyowa Chemical Industry Co., Ltd.), synthetic hydrotalside (for example, “Kyoward 500” manufactured by Kyowa Chemical Industry Co., Ltd.), synthetic magnesium silicate (for example, Kyowa Chemical Industry Co., Ltd. “Kyoward 600”), synthetic aluminum silicate (for example, Kyowa Chemical Industry Co., Ltd. “Kyoward 700”, aluminum oxide / magnesium oxide solid solution (eg, Kyowa Chemical Industry Co., Ltd. “KW-2000”), "Tomita AD700NS" manufactured by Tomita Pharmaceutical Co., Ltd.) is used, but is not limited thereto. Of these, KW-2000 is preferred because of its high ion trapping ability. The amount of the alkali adsorbent used is 0.01 to 10 times, preferably 0.1 to 8 times, more preferably 0.3 to 6 times the amount of the compound represented by the general formula (II). However, there is no particular limitation. The alkali adsorbent can be directly added to the reaction solution when the reaction between the compound represented by the general formula (I-1) and the compound represented by the general formula (I-2) is completed. Then, after the reaction is completed and the produced alkali metal salt is filtered, it may be added to the reaction solution. Although it can be removed by filtration after reacting for 0.5 to 6 hours after the addition, the reaction time is not particularly limited. As a method for using the adsorbent, the adsorbent may be added and stirred in the reaction solution as a batch type, or the reaction solution may be passed over a column packed with the adsorbent as a column type. Specific examples of the solvent for the adsorption treatment include THF, ethers such as 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, ethyl acetate, n-butyl acetate, γ-butyrolactone, etc. Examples of such esters, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile, and the like are exemplified, but are not limited thereto. In order to increase the salt adsorption capacity, aromatic hydrocarbons such as benzene, toluene and xylene are preferred. These solvents can be used alone or in combination of two or more. In that case, the mixing ratio is not particularly limited.

  When the compound represented by the general formula (II) is a solid, it can be taken out and used as a solid before moving to the next step c). In that case, the reaction solution can be crystallized as it is or after being concentrated and dropped into a poor solvent. When concentrating, it prepares so that the density | concentration of the compound represented by general formula (II) may be 10-50 mass%, for example, Preferably it is 15-45 mass%, More preferably, it is 20-40 mass%.

  When concentrating, crystallization may be performed by replacing the solvent with a good solvent of the compound represented by the general formula (II). Good solvents in that case include ethers such as THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, n-butyl acetate and γ-butyrolactone, acetone , Ketones such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile and the like can be exemplified, but are not limited thereto. These solvents can be used alone or in combination of two or more. In that case, the mixing ratio is not particularly limited. The density | concentration of the compound represented by general formula (II) after solvent substitution is 5-50 mass%, for example, Preferably it is 10-40 mass%, More preferably, it is 10-30 mass%.

  As the poor solvent, those having low solubility of the compound represented by the general formula (II) are used. For example, carbonization such as hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Hydrogen, ethers such as diethyl ether, diisopropyl ether, and di-n-butyl ether are preferably used. Although the usage-amount of a poor solvent is not specifically limited, It is 5-100 times amount with respect to the mass of the compound represented by general formula (II), Preferably it is 5-50 times amount, More preferably, it is 5-20 times amount. Use a poor solvent. The poor solvent can be used alone or in combination with another solvent. Other solvents to be mixed include esters such as ethyl acetate, n-butyl acetate and γ-butyrolactone, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, hydrocarbons such as benzene, toluene, xylene and cumene, tetrahydrofuran And ethers such as diethyl ether, 1,4-dioxane, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol monomethyl ether, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile, etc. Yes, but not limited to these.

  In step b), after solids are precipitated by crystallization, the solids may be washed and purified as necessary. The solvent used for washing is preferably the same poor solvent as described above, but is not particularly limited including the amount of washing solvent used. By drying the obtained solid under reduced pressure, the compound represented by the general formula (II) can be taken out as a solid.

When water is mixed during the polymerization of the alkylene oxide in the previous step a), a diol derivative is formed as described above, and a diol derivative represented by the following general formula (VIII) is formed through the step b). To do.
R _A ⁴ (OR _A ⁵ ) _q OR _A ⁴ (VIII)
(In the general formula (VIII), R _A ⁴ and R _A ⁵ are as defined for the general formula (II) and are the same as R _A ⁴ and R _A ^{5 in} the general formula (II). (It is an integer from 1 to 890.)

  Since the diol derivative represented by the general formula (VIII) is generated when water acts as a polymerization initiator, unlike the case where the polymerization initiator represented by the general formula (I) functions, both ends Polymerization proceeds. Therefore, q is about twice as large as r in the general formula (I-1) described above, and represents an integer of, for example, 1 to 890, preferably 20 to 790, and more preferably 40 to 690. In the present embodiment, it is possible to suppress the formation of the diol derivative as described above, preferably by performing the polymerization reaction with the water content in the reaction system kept low as described above.

  In addition, in the conventional synthesis methods described in Patent Document 4 and Patent Document 5, since the polymerization terminal is converted to a cyanoethyl group and then to an amino group, the diol impurity is finally induced to a compound having both ends at the amino group. However, since this compound has a terminal structure similar to that of the target compound, it cannot be separated by a purification method using a cation exchange resin as described later. On the other hand, in this embodiment, the diol derivative represented by the general formula (VIII) is different in terminal structure from the target compound represented by the general formula (III). For this reason, it is possible to isolate | separate by refinement | purification using the cation exchange resin which is mentioned later, for example, As a result, the polyalkylene glycol derivative (III) which has a highly purified amino group is compoundable.

[Step c)]
In step c), the protecting group in the compound represented by the general formula (II) obtained in step b) is deprotected. This deprotection is preferably performed without using a heavy metal catalyst. The heavy metal catalyst referred to here is a catalyst using, as a raw material, a heavy metal such as Co, Ni, Pd, Pt, Rh, Ru, Cu, or Cr. In step c), the deprotection method without using a heavy metal catalyst is, for example, when R _A ^1a and / or R _A ^{1b in the} general formula (II) is a silyl group (in the above (a) In the case of), under an acid catalyst, water or alcohol (R ⁶ OH: where R ⁶ is a hydrocarbon group having 1 to 5 carbon atoms) is reacted with the compound represented by the above general formula (II). Thus, it can be converted into a compound represented by the general formula (III). Specific examples and amounts of the acid catalyst to be used are as described in the second embodiment described later.

For example, when R _A ^1a and / or R _A ^1b is a tert-butyloxycarbonyl group (in the case of (A) above), a strong acid such as trifluoroacetic acid or hydrochloric acid is represented by the general formula (II). It can be deprotected by acting on the compound. The amount of these strong acids to be used is, for example, 0.01 to 1000 equivalents, preferably 0.1 to 100 equivalents, more preferably 1 to 10 equivalents, based on the number of moles of the compound represented by the general formula (II). .

For example, when R _A ^1a and R _A ^1b are N-phthaloyl groups (in the case of (U) above), by reacting hydrazine hydrate with a compound represented by the above general formula (II) in alcohol, The phthaloyl group can be eliminated. Examples of the alcohol used include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butyl alcohol. As usage-amount of alcohol, it is 1-100 times amount with respect to the mass of the compound represented by general formula (II), Preferably it is 3-50 times amount, More preferably, it is 5-10 times amount. The amount of hydrazine hydrate used is, for example, 1 to 50 equivalents, preferably 2 to 20 equivalents, more preferably 3 to 10 equivalents, in terms of the number of moles of the compound represented by the general formula (II). .

For example, when R _A ^1a and / or R _A ^1b is a benzyl group or an allyl group (in the case of (d) above), it is represented by the general formula (II) under the conditions of Birch reduction using liquid ammonium and metallic sodium. The resulting compound can be deprotected. As usage-amount of the liquid ammonium used, it is 1-100 times amount with respect to the mass of the compound represented by general formula (II), Preferably it is 3-50 times amount, More preferably, it is 5-10 times amount. It is. The amount of metallic sodium used is, for example, 2 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents, based on the number of moles of the compound represented by the general formula (II). As in the above example, deprotection can be performed by appropriately selecting conditions that do not use a heavy metal catalyst, and the conditions are not limited.

  The deprotection in step c) is preferably performed without using a heavy metal catalyst as described above, but can also be performed using a heavy metal catalyst. For example, in the case where the polyalkylene glycol derivative obtained by the production method of the present invention is used for an application (for example, cosmetics, hair restorer, surfactant, etc.) in which heavy metal contamination does not become an essential problem, step c) It is also conceivable to use such a heavy metal catalyst. When step c) is performed using a heavy metal catalyst, a general heavy metal catalyst as described above may be used in a conventional manner, and the method is not particularly limited.

  In the case of deprotection with an acid catalyst, the produced amine represented by the general formula (III) and an acid may form a salt and the acid may not be removed. At that time, when the produced basic compound is added and reacted with an acid, the added basic compound and an acid salt are formed, and the amine represented by the general formula (III) can be taken out. The salt produced at this time can be removed by filtration. If the resulting salt has been incorporated into the polymer, it can be removed using an adsorbent. As the adsorbent at that time, the adsorbent as described in the above step b) can be used, but is not particularly limited. The adsorbent is used in an amount of 0.01 to 10 times, preferably 0.1 to 8 times, more preferably 0.3 to 6 times the mass of the compound represented by formula (III). There is no particular limitation. Examples of basic compounds to be used include, but are not limited to, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, potassium methoxide and the like. The addition amount of the basic compound is, for example, 1 to 10 equivalents, preferably 1 to 5 equivalents, and more preferably 1 to 2 equivalents with respect to the number of moles of the acid catalyst used for deprotection. As the solvent for the filtration, the reaction solvent may be used as it is, or may be filtered after being replaced with a solvent in which a salt is likely to precipitate. Specific examples of the solvent in which salt is likely to precipitate include ethers such as THF, 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, ethyl acetate, n-butyl acetate, γ-butyrolactone, and the like. Examples include esters, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile, and the like, but are not limited thereto. In order to improve filterability, aromatic hydrocarbons such as benzene, toluene and xylene are preferred. These solvents can be used alone or in combination of two or more. In that case, the mixing ratio is not particularly limited.

  When removing the acid catalyst, the adsorbent can also be added directly to the reaction system without adding the basic compound, but in that case the filterability may be reduced, so after adding the above basic compound It is preferable to use an adsorbent.

  After deprotection, for example, the compound represented by the general formula (III) may be crystallized as it is with a poor solvent, or may be crystallized after substituting with a good solvent. Crystallization may be performed after the reaction with the compound and the adsorbent treatment. Specific examples of good solvents in this case include ethers such as THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, n-butyl acetate and γ-butyrolactone. , Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile and the like, but are not limited thereto. These solvents can be used alone or in combination of two or more. In that case, the mixing ratio is not particularly limited. The density | concentration after solvent substitution is 5-50 mass%, for example, Preferably it is 10-40 mass%, More preferably, it is 10-30 mass%.

  As the poor solvent used for crystallization of the compound represented by the general formula (III), a solvent having low solubility of the compound represented by the general formula (III) is used. Specific examples of the poor solvent include hydrocarbons such as hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and ethers such as diethyl ether, diisopropyl ether, and di-n-butyl ether. Used for. Although the usage-amount of a poor solvent is not specifically limited, It is 5-100 times amount with respect to the mass of the compound represented by general formula (III), Preferably it is 5-50 times amount, More preferably, it is 5-20 times amount. The solvent is used. The poor solvent can be used alone, or one or a mixture of two or more can be used. It can also be used by mixing with other solvents. Other solvents that can be mixed include esters such as ethyl acetate, n-butyl acetate and γ-butyrolactone, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, carbonization such as benzene, toluene, xylene and cumene. Hydrogens, tetrahydrofuran, diethyl ether, ethers such as 1,4-dioxane, methanol, ethanol, isopropyl alcohol, alcohols such as ethylene glycol monomethyl ether, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), Although acetonitrile etc. can be illustrated, it is not limited to these. When two or more solvents are mixed and used as the poor solvent, the mixing ratio is not particularly limited.

  In step c), a solid of the compound represented by the general formula (III) may be precipitated by crystallization, and then the solid may be washed and purified as necessary. The solvent used for cleaning is desirably the same poor solvent as described above, but is not particularly limited including the amount of the cleaning solvent used. By drying the obtained solid under reduced pressure, the compound represented by the general formula (III) can be taken out as a solid.

  In this embodiment, since the amino group of the compound represented by the general formula (III) is obtained by deprotection in the above step c), for example, a by-product that can be generated by the method described in Patent Document 5 (Compounds represented by the following (IV) to (VI)) are not substantially formed, and finally, a narrowly dispersed and high-purity polyalkylene glycol having an amino group at the terminal represented by the general formula (III) Derivatives can be synthesized. On the other hand, for example, when the cyanoethylated product is hydrogen-reduced by the method described in Patent Document 5 to lead to a polyalkylene glycol derivative having an amino group, PEG represented by the following general formula (VI) is included due to β elimination of acrylonitrile. Derivative formation cannot be prevented. In the hydrogen reduction step, the product amine is added to the imine, which is a reduction intermediate of nitrile, so that secondary and tertiary amine compounds represented by the following general formulas (IV) and (V) are by-produced. there's a possibility that. Although these side reactions can be suppressed by adding ammonia or acetic acid to the reaction system, it is difficult to completely control them by conventional methods.

（上記一般式（ＩＶ）〜（ＶＩ）中、Ｒ_Ａ ^２、Ｒ_Ａ ^３、Ｒ_Ａ ^４、Ｒ_Ａ ^５、及びｎは上記一般式（ＩＩＩ）中のＲ_Ａ ^２、Ｒ_Ａ ^３、Ｒ_Ａ ^４、Ｒ_Ａ ^５、及びｎと同一である。）

(In the general formulas (IV) to (VI), R _A ² , R _A ³ , R _A ⁴ , R _A ⁵ , and n are R _A ² , R _A ³ , R _{A in the} general formula (III). ⁴ , R _A ⁵ , and n are the same.)

[Post-processing process]
After step c), a post-treatment step can be optionally performed in which the compound represented by general formula (III) is purified using a strongly acidic cation exchange resin. In addition, when the protecting group in the compound represented by the general formula (II) obtained in step b) is a protecting group that can be deprotected with an acid, the strong acidic cation exchange resin is used after step b). By performing the post-treatment process, deprotection can be performed at the same time, and the process can be simplified. That is, in this case, the step c) (the step of obtaining the compound represented by the general formula (III) by deprotecting the compound represented by the general formula (II)) is specifically an operation of the following post-treatment step. Can be implemented.

  In the post-treatment step, the reaction product (crude product) containing the compound represented by general formula (III) obtained in step c) or the compound represented by general formula (II) obtained in step b) The reaction product (crude product) containing is reacted with a strongly acidic cation exchange resin. As a method of reacting the crude product obtained in step c) or step b) with a strongly acidic cation exchange resin, a method of flowing and adsorbing the crude product solution on a column packed with an ion exchange resin, or a resin The method of circulating the crude product solution between the cartridge filled with and the reaction tank in which step c) or step b) has been performed is mentioned, but the reaction method is not particularly limited. In addition, when a post-treatment step is performed after step b), a compound represented by the general formula (II) and water or a monohydric alcohol solvent having 1 to 5 carbon atoms are used under the catalyst of a strongly acidic cation exchange resin. , The compound represented by the general formula (III) can be adsorbed on the strongly acidic cation exchange resin after deprotection.

  Specific examples of strongly acidic cation exchange resins include Amberlite series (IR120B, IR124B, 200CT, 252) manufactured by Organo Corporation, Amberjet series (1020, 1024, 1060, 1220) manufactured by Organo Corporation, Mitsubishi Chemical Diaion series (for example, SK104, SK1B, SK110, SK112, PK208, PK212, PK216, PK218, PK220, PK228, UBK08, UBK10, UBK12, UBK510L, UBK530, UBK550), Dow Chemical Co., Ltd. DOWEX series (50W × 2 50-100, 50W × 2 100-200, 50W × 4 100-200, 50W × 8 50-100, 50W × 8 100-200, 50W × 8 200-400, HCR-S, HCR -W (H)) and the like are preferably used, but are not limited to. The amount of the strongly acidic cation exchange resin used is, for example, 1 to 50 times, preferably 1 to 30 times, more preferably 1 to 20 times the mass of the compound represented by the general formula (III). is there.

  When using a strong acidic cation exchange resin, you may use it, after processing a strong acidic cation exchange resin with an acidic compound beforehand. Strong acidic cation exchange resins are often sold in the state of alkali metal salts of sulfonic acid, and by treating with an acidic compound in advance, the sulfo group is regenerated and the reaction efficiency can be increased. Because. In this case, examples of the acidic compound used include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid, but are not limited thereto. The amount of these acidic compounds used is, for example, 1 to 15 times, preferably 1 to 10 times, more preferably 1 to 8 times the mass of the strongly acidic cation exchange resin. After treating the strongly acidic cation exchange resin with an acidic compound, the acidic compound is separated from the resin by washing with water, and water is separated with a water-soluble organic solvent such as methanol or ethanol as necessary.

  In this post-treatment step, impurities other than the compound represented by the general formula (III) (such as a compound and a salt represented by the general formula (VIII)) can be separated. That is, the crude product after step c) or step b) is reacted with a strongly acidic cation exchange resin to adsorb the compound represented by the general formula (III) to the strongly acidic cation exchange resin, and then water. Alternatively, substances other than the target compound represented by the general formula (III) can be separated by washing the strongly acidic cation exchange resin with a monohydric alcohol having 1 to 5 carbon atoms. Examples of the monohydric alcohol having 1 to 5 carbon atoms used in the washing include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and n-pentyl alcohol. Examples thereof include isopentyl alcohol and neopentyl alcohol, but are not limited thereto. When performing washing, water or a monohydric alcohol can be used alone, or a mixture of water and one or more alcohols or a mixture of two or more alcohols can be used. In that case, the mixing ratio is not particularly limited. Although the usage-amount of the water or C1-C5 monohydric alcohol to use is not specifically limited, It is 1-30 times amount with respect to the mass of the strong acidic cation exchange resin used, Preferably it is 1-20 times amount. More preferably, the amount is 1 to 10 times.

  By reacting a strongly acidic cation exchange resin adsorbed with the compound represented by the general formula (III) with a basic compound in water or a monohydric alcohol having 1 to 5 carbon atoms, the general formula (III) The compound represented is extracted into water or monohydric alcohol. In carrying out the reaction, water or a monohydric alcohol can be used alone, or a mixture of water and one or more alcohols or a mixture of two or more alcohols can be used. In that case, the mixing ratio is not particularly limited. As a method of reacting a strongly acidic cation exchange resin with a basic compound, a method of causing a solution of a basic compound to flow through a packed column and reacting, or a cartridge filled with a resin and a reaction tank in which step c) is performed Examples thereof include a method of circulating a solution of a basic compound between them, but the method of reaction is not particularly limited.

  The monohydric alcohol used in the extraction is methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, isopentyl alcohol, neopentyl alcohol. Etc. can be exemplified. Although the usage-amount of water or a monohydric alcohol is not specifically limited, It is 1-30 times amount with respect to the mass of the used strong acidic cation exchange resin, Preferably it is 1-20 times amount, More preferably, it is 1-10 times. Amount.

  As the basic compound used in the extraction, ammonia dissolved in water or an organic solvent (for example, aqueous ammonia or a methanol solution of ammonia) is preferably used. Aliphatic amines, hybrid amines, aromatic amines, heterocyclic amines and the like can also be used. Primary aliphatic amines include secondary amines such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, and ethylenediamine. Examples of tertiary aliphatic amines such as dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, and di-sec-butylamine include trimethylamine, triethylamine, and triethylamine. Examples of mixed amines such as -n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, tri-sec-butylamine include dimethylethylamine, methylethylpropylamine, benzylamino Specific examples of aromatic amines and heterocyclic amines such as phenethylamine and benzyldimethylamine include aniline derivatives (eg, aniline, N-methylaniline, N-ethylaniline, N-propylaniline, N, N-dimethylaniline). 2-methylaniline, 3-methylaniline, 4-methylaniline, ethylaniline, propylaniline, trimethylaniline, 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 2,4-dinitroaniline, 2,6 -Dinitroaniline, 3,5-dinitroaniline, N, N-dimethyltoluidine, etc.), diphenyl (p-tolyl) amine, methyldiphenylamine, triphenylamine, phenylenediamine, naphthylamine, diaminonaphthalene and pyridine derivatives (for example, pyridine, Tylpyridine, ethylpyridine, propylpyridine, butylpyridine, 4- (1-butylpentyl) pyridine, dimethylpyridine, trimethylpyridine, triethylpyridine, phenylpyridine, 3-methyl-2-phenylpyridine, 4-tert-butylpyridine, diphenyl Examples thereof include, but are not limited to, pyridine, benzylpyridine, methoxypyridine, butoxypyridine, dimethoxypyridine, 4-pyrrolidinopyridine, 2- (1-ethylpropyl) pyridine, aminopyridine, dimethylaminopyridine, and the like. Moreover, alkaline aqueous solutions, such as potassium hydroxide and sodium hydroxide, can also be used as a basic compound. The amount of the basic compound used is, for example, 0.1 to 100 times, preferably 0.1 to 10 times, more preferably 0.1 to 5 times the mass of the strongly acidic cation exchange resin used. Amount.

  Thus, by carrying out steps a) to c), or optionally, further carrying out pre-steps 1, 2 and / or post-treatment steps before and / or after steps a) to c). By doing so, a compound represented by the general formula (III) (a narrowly dispersed and high-purity polyalkylene glycol derivative having an amino group at the terminal) can be produced.

  That is, according to another aspect, the present invention relates to a narrowly dispersed and high-purity polyalkylene glycol derivative having an amino group at the terminal represented by the general formula (III) obtained by the above production method.

  General obtained after steps a) to c), or optionally obtained by further performing pre-steps 1, 2 and / or post-treatment steps before and / or after steps a) to c). In the compound represented by the formula (III), during the polymerization, the initiation reaction is sufficiently faster than the growth reaction, and there is little mixing of moisture into the reaction system, which is a cause of the termination reaction, and the polymerization initiator is contained in the polymerization solvent. Since it is uniformly dissolved, it can be obtained as a narrowly dispersed polymer. That is, the compound represented by the general formula (III) produced by the production method of the present embodiment is narrowly dispersible, and the dispersity (weight average molecular weight (Mw) / number average molecular weight (Mn)) is For example, it is 1.0-1.20, Preferably it is 1.0-1.10, More preferably, it is 1.0-1.06. In addition, the molecular weight of the compound represented by the general formula (III) produced by the production method of the present embodiment is preferably 5,000 to 25,000, preferably 8,000 to 15 as the weight average molecular weight (Mw). 1,000 is more preferable. In the present specification, the molecular weight and the degree of dispersion of the polymer refer to values when measured using gel permeation chromatography (hereinafter abbreviated as GPC).

  Production obtained after steps a) to c), or optionally, obtained by further performing pre-steps 1, 2 and / or post-treatment steps before and / or after steps a) to c). The amount of the compound represented by the general formula (IV) and the compound represented by the general formula (V) in the product is an area content (%), and the general formulas (III), (IV), and The area of the compounds represented by the general formulas (IV) and (V) is preferably 3% or less, more preferably 2% or less with respect to the total area of the compound represented by (V). Most preferably, the product obtained does not contain either the compound represented by the general formula (IV) or the compound represented by the general formula (V). In practice, according to this embodiment, neither the compound represented by the general formula (IV) nor the compound represented by the general formula (V) is generated. The secondary amine represented by the general formula (IV) and the tertiary amine represented by the general formula (V) are based on the polyalkylene glycol derivative represented by the general formula (III) which is the main product. Since it has a molecular weight of 2 times or 3 times, the production amount can be confirmed by GPC.

  Production obtained after steps a) to c), or optionally, obtained by further performing pre-steps 1, 2 and / or post-treatment steps before and / or after steps a) to c). The amount of the compound represented by the general formula (VI) in the product is 2 mol with respect to the total amount of the compound represented by the general formula (III) and the compound represented by the general formula (VI). % Or less, more preferably 1 mol% or less. Most preferably, the product obtained does not contain a compound represented by general formula (VI). In practice, according to this embodiment, the compound represented by the general formula (VI) is not generated. Since the compound represented by the general formula (VI) has an alcohol as a functional group, the polyalkylene glycol derivative represented by the general formula (III) which is a main product by proton nuclear magnetic resonance (1H-NMR). In comparison with the amine α-position methylene, the composition ratio content (mol%) can be determined.

Also obtained after steps a) to c) or optionally obtained by further performing pre-steps 1, 2 and / or post-treatment steps before and / or after steps a) to c). The product to be obtained is substantially free of by-products (compounds represented by the general formulas (IV) to (VI)) that can be produced by the conventional method as described above. Specifically, the total amount of the compound represented by the general formula (III), which is the main product, converted from the measurement results by GPC and 1H-NMR described above is X _A , the general formula (IV), the general formula (V ), And the total amount of by-products containing the compound represented by the general formula (VI) is X _B , X _A / (X _A + X _B ) is preferably 0.95 or more, more preferably 0.97 or more. Most preferably, the resulting product is free of such by-products. Actually, according to the present embodiment, these by-products are not generated.

  Also obtained after steps a) to c) or optionally obtained by further performing pre-steps 1, 2 and / or post-treatment steps before and / or after steps a) to c). The content of heavy metal impurities measured by a high frequency inductively coupled plasma mass spectrometer (ICP-MS) in the resulting product is preferably 100 ppb or less, and more preferably 10 ppb or less. The amount of heavy metal impurities in the product is generally measured using the ICP-MS, but the measurement method is not limited. When analyzing by ICP-MS, the measurement is performed by diluting the polymer sample with a solvent. It is essential that the solvent used is one that dissolves the polymer and does not contain metal. Ultrapure water and electronic industry N-methyl-2-pyrrolidone are particularly preferred, but are not limited thereto. Although a dilution rate is not specifically limited, Preferably it is 10-100,000 times, More preferably, it is 50-1,000 times.

  As described above, for example, in the conventional synthesis methods described in Patent Document 4 and Patent Document 5, since a cyano group is converted to an aminomethyl group using a Raney nickel catalyst, for example, when a polyalkylene glycol derivative is used for pharmaceutical use In such cases, there is a concern that heavy metals may be mixed into the product. According to the “ICH Q3D: Guidelines for Metal Impurities for Drugs (draft)” reported at the Japan-US EU Pharmaceutical Regulation Harmonization Conference (ICH), As, Pb, Cd, Hg, Class 2A with V, Mo, Se, Co, Class 2B with Ag, Au, Tl, Pd, Pt, Ir, Os, Rh, Ru, Class 3 with Sb, Ba, Li, Cr, Cu, Sn , Ni. Heavy metals used in hydrogen reduction reactions include Co, Ni, Pd, Pt, Rh, Ru, Cu, Cr, etc., but these are listed as heavy metals that require risk assessment. Is required. On the other hand, since the method of this embodiment does not require the use of a heavy metal catalyst as described above, no heavy metal is mixed into the product. As a result, it can be said that this is a production method suitable for obtaining a compound represented by the general formula (III) used particularly for pharmaceutical applications.

[Embodiment 2]
The present invention is represented by the compound represented by the following general formula (1) in which the amino group is protected with a silyl group and / or the following general formula (2) as the polymerization initiator among the above-described first embodiment. It is preferable to use a compound (hereinafter abbreviated and may be referred to as “a compound represented by the general formula (1) and / or (2)”. The same applies to other compounds). The compound represented by the general formula (1) and / or (2) has high solubility in a polymerization solvent, is highly stable as a polymerization initiator, and can be easily deprotected with an acid catalyst after polymerization. There are advantages. An embodiment in which the compound represented by the general formula (1) and / or (2) is used as the polymerization initiator may be hereinafter referred to as “Embodiment 2”. In addition, since this Embodiment 2 is a preferable aspect of the said Embodiment 1, below, description is abbreviate | omitted about the overlapping part.
In addition, the compound represented by the following general formula (1) is a compound represented by the general formula (I) in the first embodiment, in which R _A ^1a and R _A ^1b are each represented by Si (R ¹ ) _3. In which R _A ² is R ² and R _A ³ is (OR ⁵ ) _m .
Moreover, the compound represented by the following general formula (2) is a compound represented by the general formula (I) in the first embodiment, in which R _A ^1a and R _A ^1b are each represented by Si (R ¹ ) _3. In which R _A ² is R ³ and R _A ³ is a single bond.

  The production method of the polyalkylene glycol derivative in the case where the compound represented by the general formula (1) and / or (2) is used as the polymerization initiator in the second embodiment is described below as steps a ′) to c ′). It describes. As shown below, when the compound represented by the general formula (1) is used as a polymerization initiator, the resulting polyalkylene glycol derivative becomes a compound represented by the general formula (3), and the general formula ( When the compound represented by 2) is used, the resulting polyalkylene glycol derivative is a compound represented by the general formula (4).

Step a ′) The polymerization initiator represented by the general formula (1) and / or (2) is reacted with an alkylene oxide in a polymerization solvent, and represented by the following general formula (12) and / or (13). Obtaining a compound;
Step b ′) The compound represented by the general formula (12) and / or (13) is reacted with the compound represented by the following general formula (5), and the following general formula (14) and / or (15): And a step c ′) a compound represented by the general formula (3) and / or (4), wherein the compound represented by the general formula (14) and / or (15) is deprotected. Obtaining.

In the general formulas (1) to (2) and (12) to (15), each R ¹ is independently a straight chain having 1 to 6 carbon atoms, or a branched or cyclic structure having 3 to 6 carbon atoms. It is a monovalent hydrocarbon group. Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring together with the silicon atom to which they are bonded. Specific examples of R ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl. Group, cyclopentyl group, cyclohexyl group and the like. In addition, when R ¹ is bonded to each other to form a ring with a silicon atom, a group in which one hydrogen atom is eliminated from these groups can be mentioned. (As described above, R ¹ in the second embodiment is a separate code having a different definition from R _A ^1a and / or R _A ^{1b in the} first embodiment, and is described in the first embodiment. A) the same as R ¹ in the “protecting group having a structure represented by Si (R ¹ ) ₃ ”.) It is easy to introduce two protecting groups on nitrogen, and the general formula (described later) From the viewpoint of easy synthesis of the compound represented by 6) and / or (7), R ¹ is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

In the general formulas (1), (3), (12), and (14), R ² is a straight chain having 1 to 6 carbon atoms, or a branched or cyclic divalent having 3 to 6 carbon atoms. It is a hydrocarbon group. Specific examples of R ² include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl. And a group in which one hydrogen atom is eliminated from each of a group, a cyclopentyl group, and a cyclohexyl group. Incidentally, R ² in the present embodiment 2 corresponds to R _A ² in the above embodiment 1, its definition is the same as the definition of R _A ² in the first embodiment.

In the general formulas (2), (4), (13), and (15), R ³ is a linear divalent hydrocarbon group having 4 to 6 carbon atoms. Specific examples of R ³ include groups in which one hydrogen atom has been eliminated from each of an n-butyl group, an n-pentyl group, and an n-hexyl group. As described above, R ³ in the second embodiment is a separate code having a definition different from that of R _A ^{3 in the} first embodiment.

In the general formulas (3) to (5) and (14) to (15), R ⁴ is a hydrogen atom or a linear, branched or cyclic carbon atom having 1 to 12 carbon atoms which may be substituted. It is a hydrogen group, and the hydrocarbon group may contain a hetero atom. Specific examples of R ⁴ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, octyl group, Decyl, dodecyl, phenyl, 0-tolyl, m-tolyl, p-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl Group, 3,4-xylyl group, 3,5-xylyl group, mesityl group, vinyl group and allyl group. As R ⁴ of the substituted structure, for example, an acetalized formyl group, a cyano group, a formyl group, a carboxyl group, an amino group, an alkoxycarbonyl group having 1 to 6 carbon atoms, an acylamide group having 2 to 7 carbon atoms, the same or Different tri (C 1-6 alkyl) siloxy groups, siloxy groups, silylamino groups, maleimide groups, thiol groups, hydroxyl groups, methacryloyloxy groups, acryloyloxy groups, active ester groups, and azide groups. Specific examples of R _A ⁴ having a substituent include, but are not limited to, those represented by the following structural formula. The following formula shows the terminal portion of R ⁴ of the substituted structure, and the dotted line in the formula indicates that the hydrocarbon portion of R ⁴ can take variations as exemplified above. Such substituents may be further protected with any appropriate protecting group.

Incidentally, R ⁴ in the present embodiment 2 corresponds to R _A ⁴ in the above embodiment 1, its definition is the same as the definition of R _A ⁴ in the first embodiment.

In the general formulas (1), (3) to (5) and (12) to (15), R ⁵ is an alkylene group having 2 to 8 carbon atoms. Among these, an alkylene group having 2 to 3 carbon atoms is preferable. That is, R ⁵ is preferably an ethylene group or a propylene group. The (OR ⁵ ) unit may be composed of only one kind of oxyalkylene group, for example, an oxyethylene group or an oxypropylene group, or two or more kinds of oxyalkylene groups may be mixed. When two or more kinds of oxyalkylene groups are mixed, (OR ⁵ ) may be one obtained by randomly polymerizing two or more different oxyalkylene groups, or one obtained by block polymerization. Incidentally, R ⁵ in the present embodiment 2 corresponds to R _A ⁵ in the above embodiment 1, its definition is the same as the definition of R _A ⁵ in the first embodiment.

  In the general formulas (1) to (2) and (12) to (13), M represents an alkali metal, and specific examples of M are as described in the first embodiment.

  In the general formulas (1), (3), (12) and (14), m represents an integer of 1 to 3. Considering the boiling point of the compound during distillation, m is preferably an integer of 1 to 2.

  In the general formulas (1) to (4) and (12) to (15), r, k, n, and L are the same as r, k, n, and L described in the first embodiment. is there.

In the selection of each compound used in each step of the production method of Embodiment 2, the general formula (3) and / or (4), which is a desired final product, can be obtained. In 1), (2), (5), and (12) to (15), select desired R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, r, k, n, and L can do.

  In the second embodiment, prior to steps a ′) to c ′), [previous step 1 ′] and [previous step 2 ′] can be performed as optional steps. [Pre-Step 1 ′] and [Pre-Step 2 ′] are steps for producing a compound represented by the following general formula (6) and / or (7), which is a raw material (starting material) of the polymerization initiator ( Step 1 ′]) and a step of producing a compound represented by the above general formula (1) and / or (2) which is a polymerization initiator ([Pre-Step 2 ′]). As the previous step, [Previous step 2 ′] may be performed following [Previous step 1 ′], or only [Previous step 2 ′] may be performed without passing through [Previous step 1 ′]. .

  In the second embodiment, after the steps a ′) to c ′), as an optional step, the obtained target product (compound represented by the general formula (3) and / or (4)) is used. You may perform the post-processing process which refine | purifies.

  In the following description of the preferred embodiment 2, description will be made in the order of [Pre-process 1 '] and [Pre-process 2'], Process a ') to Process c'), and Post-processing process in time series. In addition, about the location of the content similar to above-mentioned Embodiment 1, description is abbreviate | omitted suitably.

[Previous process 1 ']
[Pre-process 1 ′] is a process for synthesizing a compound represented by the following general formula (6) and / or (7) used as a precursor of the polymerization initiator.

（上記一般式（６）及び（７）中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍは、上記一般式（１）及び（２）について定義したとおりであって、上記一般式（１）及び（２）中のＲ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍと同一である。）

(In the above general formulas (6) and (7), R ¹ , R ² , R ³ , R ⁵ , and m are as defined for the above general formulas (1) and (2). (It is the same as R ¹ , R ² , R ³ , R ⁵ , and m in (1) and (2).)

  [Pre-process 1 ′] can be carried out, for example, in the following processes (1-1) to (1-2) and the following processes (2-1) to (2-2), but is not limited thereto. It is not a thing.

（上記一般式（６ａ）、（６ｂ）、（７ａ）、（８）、及び（９）中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍは、一般式（１）及び（２）について定義したとおりであって、一般式（１）及び（２）中のＲ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍと同一である。Ｌ^１は脱離基を表し、その具体例は上記実施形態１に記載したとおりである。Ｒ^６は炭素数１〜５の炭化水素基である。）

(In the general formulas (6a), (6b), (7a), (8), and (9), R ¹ , R ² , R ³ , R ⁵ , and m are represented by the general formulas (1) and (2 And is the same as R ¹ , R ² , R ³ , R ⁵ , and m in the general formulas (1) and (2), L ¹ represents a leaving group, Examples are as described in Embodiment 1. R ⁶ is a hydrocarbon group having 1 to 5 carbon atoms.

Specific examples of R ⁶ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and the like. However, it is not limited to these.

  Since the silicon-nitrogen bond is generally weaker than the silicon-oxygen bond, in the deprotection reaction represented by the above formulas (1-2) and (2-2), the silicon-nitrogen bond is primarily preferred. Is cut off. However, in the case of this reaction in the present embodiment 2, since two bulky protective groups (trialkylsilyl groups) exist on nitrogen, the silicon-oxygen bond can be preferentially cut by the steric hindrance. Thus, after protecting the amino group with two bulky protecting groups and also protecting the hydroxy group with one protecting group of the same structure (ie, all three protecting groups were applied at the amino and hydroxy groups). Later, by utilizing the bulkiness of the amino group having two protective groups, deprotection preferentially only on the hydroxy group, which was difficult in the conventional method, an alcohol in which only the amino group was silylated Can be synthesized.

  The implementation of the step (1-1) and / or (2-1) can be performed, for example, as follows. A basic compound may be added to the compound represented by the general formula (6a) and / or (7a) without a solvent, and then the compound represented by the general formula (6b) may be dropped and mixed to be reacted. The basic compound is added after dissolving the compound represented by the general formula (6a) and / or (7a) in an appropriate solvent, and then the compound represented by the general formula (6b) is dropped. You may make it react by mixing. The amount of the compound represented by the general formula (6b) is, for example, 3 to 15 times, preferably 3 to 10 times the number of moles of the compound represented by the general formula (6a) and / or (7a). The amount is more preferably 3 to 5 times.

  When a solvent is used in the step (1-1) and / or (2-1), specific examples of the solvent include ethers such as THF and 1,4-dioxane, aromatics such as benzene, toluene, and xylene. Nonlimiting examples include hydrocarbons, halogens such as methylene chloride, N, N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, acetone, and the like. Although the usage-amount of a solvent is not specifically limited, It is 1-20 times amount with respect to the mass of the compound represented by General formula (6a) and / or (7a), Preferably it is 2-10 times amount, More preferably Is 2 to 5 times the amount.

  Specific examples of the basic compound used in the step (1-1) and / or (2-1) include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, sodium carbonate, Carbonates such as potassium carbonate and cesium carbonate, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, metal hydrides such as sodium hydride and potassium hydride, primary, secondary, Tertiary aliphatic amines, hybrid amines, aromatic amines, heterocyclic amines, aqueous ammonia and the like can be used, but are not limited thereto. The amount of the basic compound used is, for example, 3 to 15 times, preferably 3 to 10 times, more preferably 3 with respect to the number of moles of the compound represented by the general formula (6a) and / or (7a). ~ 5 times the amount.

  Although the reaction temperature in the said process (1-1) and / or (2-1) can be performed within the range of melting | fusing point-boiling point of the solvent to be used, for example, -60 degreeC-150 degreeC, Preferably it is 0 degreeC- 80 ° C. The end of the reaction is the main product when the compound represented by the general formula (6a) and / or (7a) disappears by gas chromatography or the compound represented by the general formula (8) and / or (9). Can be obtained as

Moreover, the said process (1-2) and / or (2-2) can be implemented by base-treating the compound represented, for example by General formula (8) and / or (9). Specifically, for example, it can be carried out as follows. Once the compound represented by the general formula (8) and / or (9) is purified and taken out, the compound represented by the general formula (8) and / or (9) is dissolved in R ⁶ OH to obtain a catalyst. An amount of R ⁶ ONa is added to effect selective deprotection. The generated (R ¹ ) ₃ SiOR ⁶ is distilled off under reduced pressure together with R ⁶ OH, so that the equilibrium is biased from the general formula (8) and / or (9) to the general formula (6) and / or (7). The reaction can be completed by adding R ⁶ OH again for further reaction, and repeating the above-described operation of distilling off under reduced pressure. The amount of R ⁶ OH, especially but not limited to, the general formula (8) and / or (9) mass relative to example 1-20 times the amount of the compound represented by the, preferably 2 to 15 times, More preferably, the amount is 3 to 10 times. The amount of R ⁶ ONa is not particularly limited with respect to the number of moles of the compound represented by the general formula (8) and / or (9), for example 0.01 times, preferably 0.01 -0.5 times the amount, more preferably 0.01-0.1 times the amount.

  The reaction temperature in the said process (1-2) and / or (2-2) is 0 degreeC-100 degreeC, for example, Preferably it is 30 degreeC-80 degreeC. The reaction can be completed at the time when the compound represented by the general formula (8) and / or (9) disappears by gas chromatography. The compound represented by the general formula (6) and / or (7) is preferably purified by distillation to remove water. In this case, the water content of the compound represented by the general formula (6) and / or (7) is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less.

  As another method for producing the compound represented by the general formula (6) and / or (7), for example, the following steps (1-3) to (1-4) and the following steps (1-5) to (1) -6), methods such as the following steps (2-3) to (2-4) may be mentioned, but are not limited thereto.

（上記一般式（６ｂ）、（６ｃ）、（６ｄ）、（６ｅ）、（６ｆ）、（７ｂ）、及び（７ｃ）中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍは、一般式（１）及び（２）について定義したとおりであって、一般式（１）及び（２）中のＲ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍと同一である。Ｌ^１、Ｌ^２はそれぞれ脱離基を表し、その具体例は上記実施形態１に記載したとおりである。ＴｓＣｌは塩化ｐ−トルエンスルホニルの略であり、ＭｓＣｌは塩化メタンスルホニルの略である。）

(In the general formulas (6b), (6c), (6d), (6e), (6f), (7b), and (7c), R ¹ , R ² , R ³ , R ⁵ , and m are be as defined for the general formula (1) and (2), the general formula (1) and (2) of ^{R 1, R 2, R 3} , .L 1 R 5, and is identical to m, L ² represents a leaving group, and specific examples thereof are as described in Embodiment 1. TsCl is an abbreviation for p-toluenesulfonyl chloride, and MsCl is an abbreviation for methanesulfonyl chloride.)

The steps (1-3) and (2-3) can be performed by the same method as the step (i-2) described in the first embodiment.
The above steps (1-4) and (1-6) can be carried out in the same manner as in step (i-3) described in the first embodiment. In the case of the reactions represented by the above (1-4) and (1-6), as described in the step (i-3) of Embodiment 1, the use of an excessive amount of diol gives priority to one terminal. The alcohol can be etherified.

  The above step (1-5) can be performed, for example, as follows. Using (6e) synthesized by the same method as in step (i-1) described in Embodiment 1 above as a starting material, a basic compound is added to the compound represented by general formula (6e) without solvent, and then The reaction may be performed by adding and mixing TsCl or MsCl, or adding a basic compound after dissolving the compound represented by the general formula (6e) in an appropriate solvent, and then adding TsCl or MsCl. You may make it react by adding and mixing. The amount of TsCl or MsCl used is, for example, 1 to 5 times, preferably 1 to 3 times, more preferably 1 to 2 times the number of moles of the compound represented by the general formula (6e). It is.

  When a solvent is used in the above step (1-5), specific examples of the solvent include ethers such as THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, and methylene chloride. Examples include, but are not limited to, halogens, N, N-dimethylformamide, N-methyl-2-pyrrolidone, and acetonitrile. Although the usage-amount of a solvent is not specifically limited, It is 1-20 times amount with respect to the mass of the compound represented by General formula (6e), Preferably it is 2-10 times amount, More preferably, it is 2-5 times amount. It is.

  Specific examples of the basic compound used in the above step (1-5) include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, and carbonates such as sodium carbonate, potassium carbonate and cesium carbonate. Metal alkoxides such as salts, sodium methoxide, sodium ethoxide, potassium t-butoxide, metal hydrides such as sodium hydride and potassium hydride, primary, secondary and tertiary aliphatic amines Hybrid amines, aromatic amines, heterocyclic amines, aqueous ammonia and the like can be used, but are not limited thereto. The amount of the basic compound used is, for example, 3 to 15 times, preferably 3 to 10 times, more preferably 3 to 5 times the number of moles of the compound represented by the general formula (6e). .

  Although the reaction temperature in the said process (1-5) can be performed within the range of melting | fusing point-boiling point of the solvent to be used, it is -60 degreeC-150 degreeC, for example, Preferably it is 0 degreeC-80 degreeC. The reaction can be completed at the time when the compound represented by the general formula (6e) disappears by gas chromatography.

  The above step (2-4) can be performed, for example, as follows. The compound represented by the general formula (7c) synthesized in the above step (2-3) may be reacted by adding a sodium hydroxide aqueous solution without solvent using the compound represented by the general formula (7c) as a starting material, and mixing them. After dissolving the compound represented by the general formula (7c), an aqueous sodium hydroxide solution may be added and mixed to react. The amount of sodium hydroxide used is, for example, 1 to 5 times, preferably 1 to 3 times, more preferably 1 to 2 times the number of moles of the compound represented by the general formula (7c). is there.

  When a solvent is used in the above step (2-4), specific examples of the solvent include ethers such as H2O, THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, methylene chloride. Halogens such as N, N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile and the like, but are not limited thereto. Although the usage-amount of a solvent is not specifically limited, It is 1-20 times amount with respect to the mass of the compound represented by General formula (7c), Preferably it is 2-10 times amount, More preferably, it is 2-5 times amount. It is.

  Although the reaction temperature in the said process (2-4) can be performed within the range of melting | fusing point-boiling point of the solvent to be used, it is -60 degreeC-100 degreeC, for example, Preferably it is -30 degreeC-20 degreeC. The reaction can be completed at the time when the compound represented by the general formula (7c) disappears by gas chromatography.

[Previous process 2 ']
[Previous Step 2 ′] is a reaction of the compound represented by the above general formula (6) and / or (7) with an alkali metal or an alkali metal compound, thereby allowing the following general formula (1) and / or ( In this step, the compound represented by 2) is obtained.

  The reaction of [Pre-process 2 '] can be carried out in the same manner as in Pre-process 2 of Embodiment 1. That is, the type and amount of alkali metal or alkali metal compound to be used, the type and amount of solvent to be used, the method of adding the compound to the reaction system, the reaction temperature, etc. are the same as those in the previous step 2 of Embodiment 1 above. It can select suitably in the described range. In addition, as the solvent used in [Previous Step 2 ′], whether or not the polymerization initiator is dissolved in the polymerization solvent at the time of synthesis of the polymerization initiator by using the same kind of the polymerization solvent used in the polymerization, This can be confirmed in advance. The confirmation method is the same as that described in the previous step 2 of the first embodiment.

As described above, when the polymerization reaction is performed, a reaction system including a compound (polymerization initiator) represented by the general formula (1) and / or (2) in order to suppress the formation of a diol polymer as a by-product. It is preferable to keep the moisture in the inside as low as possible. In this regard, for example, the compound represented by the general formula (6) has a boiling point as high as 120 ° C. (10 Pa) when R ¹ = ethyl group, R ² = CH ₂ CH ₂ CH ₂ , m = 1, The compound represented by the general formula (7) has a boiling point as high as 110 ° C. (10 Pa) in the case of R ¹ = ethyl group and R ³ = CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ , and the difference in boiling point from water Therefore, water can be separated by drying under reduced pressure. Therefore, in [Previous Step 2 ′], the compound represented by the general formula (6) and / or (7) is sufficiently dried under reduced pressure before the addition of the alkali metal or the alkali metal compound, and then distilled. It is preferable to carry out. The range of the moisture content of the compound represented by the general formula (6) and / or (7) is the range of the moisture content of the compound represented by the general formula (i) described in the previous step 2 of Embodiment 1 above. It is the same.

  As described above, in order to improve the polymerization rate, it is preferable to use a polymerization initiator with a small amount of initiator raw material alcohol remaining. Specifically, after completion of the synthesis of the polymerization initiator in [Previous Step 2 ′], the polymerization initiator represented by the general formula (1) and / or (2) and the general formula (6) and / or (7 The substance amount ratio with the initiator raw material alcohol represented by () is represented by the polymerization initiator represented by the general formula (I) described in the preceding step 2 of the first embodiment and the general formula (i). It is preferable to be in the same range as the substance amount ratio of the starting raw material alcohol. Moreover, after synthesizing the above-described polymerization initiator, the initiator raw alcohol represented by the general formula (6) and / or (7) can be distilled off under reduced pressure. In that case, the general formula (1) And / or the mass ratio of the polymerization initiator represented by (2) and the initiator raw alcohol represented by the general formula (6) and / or (7) is also the same as that in the previous step 2 of the first embodiment. It is preferable that it is the same range as the substance amount ratio of the polymerization initiator represented by the general formula (I) and the initiator raw material alcohol represented by the general formula (i).

[Step a ′)]
Step a ′) is a step of reacting the compound represented by the general formula (1) and / or (2) with an alkylene oxide in a polymerization solvent. Desirably, the compound represented by the general formula (1) and / or (2) is completely dissolved in the polymerization solvent and then reacted with the alkylene oxide. According to step a ′), a compound represented by the following general formula (12) and / or (13) can be obtained. As the polymerization initiator, only one of the compound represented by the general formula (1) or the compound represented by the general formula (2) may be used, or both may be used in combination. May be.

Here, since the silicon-oxygen bond is generally stronger than the silicon-nitrogen bond, when a 5-membered or 6-membered ring structure containing a silicon-oxygen bond can be formed, There is a possibility that the exchange reaction between the silicon-nitrogen bond and the silicon-oxygen bond proceeds. Therefore, for example, even when polymerization is attempted using the compound represented by the following formula (0a) as a polymerization initiator, the polymerization proceeds from the amino group side instead of the alkoxide side, and the target polyalkylene glycol derivative is I can't get it. On the other hand, in the polymerization initiator represented by the general formula (1) and / or (2) used in the second embodiment (for example, the following formulas (1a) and (2a)), nitrogen, O ⁻ By extending the chain length of the chain connecting with oxygen constituting M ⁺ to 4 or more, generation of a 5-membered or 6-membered ring structure containing a silicon-oxygen bond is suppressed, and the state is stable in an alkoxide state. Can be formed. As a result, polymerization proceeds from the alkoxide side, and the desired polyalkylene glycol derivative can be obtained.

Since the silyl-protected amino group-containing alcohol derivative represented by the general formula (1) and / or (2) used as a polymerization initiator has a structure similar to that of the polymerization solvent in the structure of each molecule, It can be dissolved in the polymerization solvent without being present. In particular, the polymerization initiator represented by the general formula (1) has an alkylene oxide structure in the molecule so that, for example, when the solvent is an ether solvent such as THF, the phase of the polymerization initiator and the polymerization solvent. Solubility increases and the polymerization initiator can be dissolved in the polymerization solvent without the presence of the initiator raw alcohol. In particular, for the polymerization initiator represented by the general formula (2), by having the hydrocarbon structure represented by R ³ in the molecule, for example, when the solvent is a hydrocarbon solvent such as toluene, The compatibility between the polymerization initiator and the polymerization solvent is increased, and the polymerization initiator can be dissolved in the polymerization solvent without the presence of the initiator raw material alcohol. As a result, it is possible to carry out polymerization under a uniform system and mild conditions, and it becomes possible to produce a narrowly dispersed polyalkylene glycol derivative.

  The reaction of step a ′) can be carried out in the same manner as described in step a) of Embodiment 1 above. That is, the type of polymerization solvent to be used, the amount thereof used, the method of adding alkylene oxide to the reaction system, the reaction temperature, and the like can be appropriately selected within the range described in step a) of the above embodiment.

  Among these, when the polymerization initiator represented by the general formula (1) is used, since it has an alkylene oxide structure in the molecule, the polymerization solvent is a cyclic ether compound having 4 to 10 carbon atoms or a straight chain. Alternatively, a branched ether compound is preferably used. Specific examples of the cyclic ether compound and the linear or branched ether compound are as described in Step a) of Embodiment 1 above. Moreover, when using the polymerization initiator represented by General formula (2), since it has a hydrocarbon structure in a molecule | numerator, aromatic hydrocarbons are used preferably as a polymerization solvent. Specific examples thereof are also as described in step a) of the above embodiment.

[Step b ′)]
Step b ′) is a step of reacting the compound represented by the general formula (12) and / or (13) obtained in the step a ′) with a compound represented by the following general formula (5). . By step b ′), compounds represented by the following general formulas (14) and (15) can be obtained.
R ⁴ (OR ⁵ ) _k L (5)

  The reaction of step b ') can be carried out in the same manner as described in step b) of Embodiment 1 above. That is, the method of adding the compound represented by the general formula (5) to the reaction system, the type and amount of the solvent used, the type and amount of the base catalyst used, the type of the alkali adsorbent used and The amount used, reaction temperature, crystallization, washing, purification, etc. of the compound represented by the general formula (14) and / or (15) obtained are within the range described in step b) of the above embodiment. It can be selected appropriately.

[Step c ′)]
In step c ′), the compound represented by the general formula (14) and / or (15) obtained in step b ′) is deprotected. This deprotection is preferably performed without using a heavy metal catalyst. More preferably, the compound represented by the general formula (14) and / or (15) is deprotected under acidic conditions. Specifically, the compound represented by the general formula (14) and / or (15) is subjected to water or alcohol (R ⁶ OH: where R ⁶ is a carbon atom having 1 to 5 carbon atoms) in the presence of an acid catalyst. And a compound represented by the following general formula (3) and / or (4). The reaction is carried out by reacting the compound represented by the general formula (14) and / or (15) with water or an alcohol in the presence of an acid catalyst in the absence of a solvent or in an appropriate solvent as necessary. It can be carried out. At that time, since the yield can be improved by moving the equilibrium to the product side, the (R ¹ ) ₃ SiOH or (R ¹ ) ₃ SiOR ^{6 to be produced} is heated or under reduced pressure. It is preferable to distill off. Although the usage-amount of water or alcohol is not specifically limited, For example, 2-4000 equivalent with respect to the number-of-moles of General formula (14) and / or (15), Preferably it is 10-3000 equivalent, More preferably, it is 20-2000 equivalent It is.

  Specific examples of the acid catalyst to be used include formic acid, acetic acid, propionic acid, succinic acid, citric acid, tartaric acid, fumaric acid, malic acid, trifluoroacetic acid and other carboxylic acids, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchlorine Examples thereof include inorganic acids such as acids, sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, and solid acids such as Amberlyst series manufactured by Organo Corporation, but are not limited thereto. The amount of these acid catalysts used is, for example, 0.01 to 500 equivalents, preferably 0.1 to 300 equivalents, more preferably the number of moles of the compound represented by the general formula (14) and / or (15). Is 0.1 to 150 equivalents. These acidic compounds can be used alone or in combination of one or more. In that case, the mixing ratio is not particularly limited.

  Crystallization, washing, purification, etc. of the compound represented by the general formula (3) and / or (4) obtained after deprotection are appropriately selected within the range described in the step c) of the first embodiment. Can be implemented.

  Since the amino group of the compound represented by the general formula (3) and / or (4) is obtained by deprotection in the step c ′), for example, a by-product (described below) that can be generated by the method described in Patent Document 5 (A compound represented by (A) to (C-2)) is not produced, and finally has a narrow dispersion and high purity having an amino group at the terminal represented by the general formula (3) and / or (4) Polyalkylene glycol derivatives can be synthesized. On the other hand, when using the method of patent document 5, for example, as mentioned above, the production | generation of the PEG derivative shown by the following general formula (A) cannot be prevented. In the hydrogen reduction step, secondary and tertiary amine compounds represented by the following general formulas (B-1), (B-2), (C-1), and (C-2) may be by-produced. There is. These side reactions are difficult to completely control by conventional methods as described above.

（上記一般式（Ａ）、（Ｂ−１）、（Ｂ−２）、（Ｃ−１）、（Ｃ−２）中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、ｍ、及びｎは、一般式（３）及び（４）について定義したとおりであって、一般式（３）及び（４）のＲ^２、Ｒ^３、Ｒ^４、ｍ、及びｎと同一である。）

(In the above general formulas (A), (B-1), (B-2), (C-1), (C-2), R ² , R ³ , R ⁴ , R ⁵ , m, and n are As defined for general formulas (3) and (4), which are the same as R ² , R ³ , R ⁴ , m, and n in general formulas (3) and (4).

[Post-processing process]
After step c ′), a post-treatment step for purifying the compound represented by the general formula (3) and / or (4) using a strongly acidic cation exchange resin can be performed. In this case, the post-processing step can also be performed by the same operation as described in the post-processing step of the first embodiment.

  Thus, by performing steps a ′) to c ′) (or optionally before and / or after steps a ′) to c ′), the previous steps 1 ′, 2 ′ and / or By further performing a post-treatment step), a compound represented by the general formula (3) and / or (4) (a narrowly dispersed and high-purity polyalkylene glycol derivative having an amino group at the terminal) can be produced. it can.

  That is, according to another aspect of the present invention, a narrowly dispersed and high-purity polyalkylene glycol having an amino group at the terminal represented by the general formula (3) and / or (4) obtained by the above production method. It relates to derivatives.

  Further after the steps a ′) to c ′) (or optionally before and / or after steps a ′) to c ′) Properties of the compound represented by the general formula (3) and / or (4) obtained by the implementation, that is, dispersity and weight average molecular weight, by-products (PEG derivatives and secondary and tertiary amines) The mixing amount, heavy metal impurity content, and the like are the same as those described for the compound represented by the general formula (III) in the first embodiment.

  According to still another aspect, the present invention is represented by the above general formula (I) used as a polymerization initiator for use in the method for producing a polyalkylene glycol derivative having an amino group at the terminal end disclosed above. The present invention relates to a metal salt of a protected amino group-containing alcohol compound. Especially, it is preferable that it is a metal salt of the novel silyl protection amino group containing alcohol compound represented by the said General formula (1) or (2). The present invention further relates to a novel protected amino group-containing alcohol compound represented by the above general formula (i), which is used as a raw material (starting material) of the polymerization initiator. Especially, it is preferable that it is a novel silyl protection amino group containing alcohol compound represented by the said General formula (6) or (7). Since the definition, production method, and use method of these compounds have been described in detail in the production method of the polyalkylene glycol derivative in Embodiment 1 and Embodiment 2, the description thereof is omitted.

EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In addition, in the description of the molecular weight in an Example, the numerical value of a weight average molecular weight (Mw) and a number average molecular weight (Mn) is measured as a polyethylene glycol conversion value by gel permeation chromatography (GPC). GPC was measured under the following conditions.
Column: TSKgel SuperAWM-H, SuperAW-3000
Developing solvent: DMF (Liquid bromide 0.01 mol / L solution)
Column oven temperature: 60 ° C
Sample concentration: 0.20 wt%
Sample injection volume: 25 μl
Flow rate: 0.3 ml / min

[Synthesis Example 1] Synthesis of compound represented by formula (iA)
Synthesis Example 1-1 Synthesis of Compound Represented by Formula (iA-1) A 50 ml three-necked flask was charged with 0.75 g of 2- (3-aminopropoxy) -ethanol, 2.35 g of triethylamine, and 2.92 g of toluene. Thereafter, 5.98 g of triethylsilyl trifluoromethanesulfonate (hereinafter referred to as TESOTf) was added dropwise in a nitrogen atmosphere. Thereafter, the mixture was stirred at 80 ° C. for 25 hours. The reaction solution was transferred to a separatory funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 2.71 g (yield: 93.3%) of the silyl protector (iA-1).
Cyril protector (iA-1)
Colorless liquid Boiling point 190 ° C / 10Pa
¹ H-NMR (500 MHz, CDCL3): δ = 0.63 (18H, q), 0.96 (27H, t), 1.69 (2H, m), 2.83 (2H, m), 3. 40 (2H, t), 3.49 (2H, t), 3.76 (2H, t)

式中ＴＥＳはトリエチルシリル基のことである。

In the formula, TES is a triethylsilyl group.

Synthesis Example 1-2 Synthesis of Compound Represented by Formula (iA) A 10 ml eggplant flask was charged with 2.21 g of silyl protector (iA-1), 2.70 g of methanol, 13 mg of sodium methoxide, and 18 at 60 ° C. Stir for hours. Thereafter, triethylmethoxysilane was distilled off under reduced pressure, and 2.70 g of methanol was added again, followed by stirring at 60 ° C. The same operation was repeated. After the reaction was completed, the reaction was quenched with sodium hydrogen carbonate, and the solvent was replaced with toluene, and then the salt was removed by filtration. Thereafter, distillation was performed under reduced pressure to obtain 1.50 g (yield 90.0%) of a silyl-protected amino group-containing alcohol (iA). As a result of measuring the water content after distillation, the water content was 1 ppm or less.
Silyl-protected amino group-containing alcohol (iA)
Colorless liquid Boiling point 118-122 ° C / 10Pa
¹ H-NMR (500 MHz, CDCL3): δ = 0.60 (12H, q), 0.93 (18H, t), 1.68 (2H, m), 1.96 (1H, bs), 2. 82 (2H, m), 3.40 (2H, t), 3.50 (2H, m), 3.73 (2H, m)

[Synthesis Example 2] Synthesis of Formula (iA) by Alternative Method [Synthesis Example 2-1] Synthesis of Electrophile (iiA) (2-1-1) Synthesis of Silyl Protector (iiA-1) In a 300 ml three-necked flask 6.0 g of 3-amino-1-propanol, 28.74 g of triethylamine, and 18.0 g of toluene were charged, and then 75.0 g of TESOTf was added dropwise under a nitrogen atmosphere. Thereafter, the mixture was stirred at 80 ° C. for 25 hours. The reaction solution was transferred to a separatory funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 31.47 g (yield: 93.3%) of a silyl protector (iiA-1).
Cyril protected body (iiA-1)
Colorless liquid Boiling point 133-138 ° C / 10Pa
¹ H-NMR (500 MHz, CDCL3): δ = 0.60 (18H, q), 0.94 (27H, t), 1.62 (2H, m), 2.83 (2H, m), 3. 54 (2H, t)

(2-1-2) Synthesis of silyl protected amino group-containing alcohol (iiA-2) A 200 ml eggplant flask was charged with 30.98 g of silyl protected (iiA-1), 30.98 g of methanol, and 0.2 g of sodium methoxide. And stirred at 60 ° C. for 18 hours. Thereafter, triethylmethoxysilane was distilled off under reduced pressure, and 30.98 g of methanol was added again, followed by stirring at 60 ° C. The same operation was repeated. After the reaction was completed, the reaction was quenched with sodium hydrogen carbonate, and the solvent was replaced with toluene, and then the salt was removed by filtration. Thereafter, toluene was distilled off under reduced pressure to obtain 22.66 g (crude yield 96.4%) of a silyl-protected amino group-containing alcohol (iiA-2). ^Since it was confirmed by ¹ H-NMR spectrum that this crude product had sufficient purity as an intermediate, (iiA-2) was directly used in the next step.
Silyl-protected amino group-containing alcohol (iiA-2)
Colorless liquid
¹ H-NMR (500 MHz, CDCL3): δ = 0.60 (12H, q), 0.93 (18H, t), 1.67 (2H, m), 2.85 (2H, m), 3. 59 (2H, m)

(2-1-3) Synthesis of electrophile (iiA) A 50 ml three-necked flask was charged with 4.7 g of TsCl, 5 g of methylene chloride, and 5.0 g of triethylamine, and 5.0 g of a silyl-protected amino group-containing alcohol (iiA-2) was added. A solution dissolved in 10.0 g of methylene chloride was added dropwise while cooling with ice. After returning to normal temperature and stirring for 13 hours, it was quenched with water and extracted with toluene. Thereafter, the toluene solution was concentrated to obtain 7.6 g of electrophile (iiA) (crude yield: 100%). ^Since it was confirmed by ¹ H-NMR spectrum that this crude product had sufficient purity as an intermediate, (iiA) was directly used in the next step.
Electrophile (iiA)
Brown liquid
¹ H-NMR (500 MHz, CDCL3): δ = 0.54 (12H, q), 0.89 (18H, t), 1.68 (2H, m), 2.45 (3H, s), 2. 71 (2H, m), 3.98 (2H, t)

[Synthesis Example 2-2] Synthesis of electrophile (iiB) In a 200 ml three-necked flask, 15.93 g of 3-bromopropylamine hydrobromide, 27.26 g of triethylamine, and 47.79 g of toluene were charged, and then the atmosphere was changed to a nitrogen atmosphere. TESOTf50.00g was dripped. Thereafter, the mixture was stirred at 80 ° C. for 63 hours. The reaction solution was transferred to a separatory funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 8.00 g of electrophile (iiB) (yield 30.0%).
Electrophile (iiB)
Colorless liquid Boiling point 108 ° C / 30Pa
¹ H-NMR (500 MHz, CDCL3): δ = 0.61 (12H, q), 0.94 (18H, t), 1.92 (2H, m), 2.90 (2H, m), 3. 31 (2H, t)

Synthesis Example 2-3 Synthesis of Compound Represented by Formula (iA) Using Electrophile (iiA) Ethylene glycol 6.78 g, N-methylpyrrolidone 10 g, potassium tert-butoxide 1.35 g in a 100 ml three-necked flask After stirring for 30 minutes, a solution of 5.0 g of electrophile (iiA) dissolved in 15 g of N-methylpyrrolidone was added dropwise at room temperature. After raising the temperature to 60 ° C. and stirring for 5 hours, the reaction was stopped with 0.18 g of sodium hydrogen carbonate. Subsequently, the solvent was replaced with diphenyl ether, and the precipitated salt was removed by filtration. Thereafter, the residue was distilled under reduced pressure to obtain 3.16 g (yield 65.7%) of a silyl-protected amino group-containing alcohol (iA). As a result of measuring the water content after distillation, the water content was 1 ppm or less (the water content was measured with a Karl Fischer moisture meter).
Silyl-protected amino group-containing alcohol (iA)
Colorless liquid Boiling point: The same result as obtained in [Synthesis Example 1-2] above.
¹ H-NMR (500 MHz, CDCL3): same result as obtained in [Synthesis Example 1-2] above.

式中Ｔｓはパラトルエンスルホニル基、ｔ−ＢｕＯＫはカリウムｔｅｒｔ−ブトキシド、ＮＭＰはＮ−メチルピロリドンのことである。

In the formula, Ts is a paratoluenesulfonyl group, t-BuOK is potassium tert-butoxide, and NMP is N-methylpyrrolidone.

[Synthesis Example 2-4] Synthesis of Compound Represented by Formula (iA) Using Electrophile (iiB) 2.98 g of ethylene glycol, 5.0 g of N-methylpyrrolidone, potassium tert-butoxide 0 in a 200 ml three-necked flask .54 g was charged, and after stirring for 30 minutes, a solution prepared by dissolving 2.00 g of electrophile (iiB) in 10.0 g of N-methylpyrrolidone was added dropwise at room temperature. After heating up to 60 degreeC and stirring for 5 hours, the reaction was stopped using 0.08 g of sodium hydrogencarbonate. Subsequently, the solvent was replaced with diphenyl ether, and the precipitated salt was removed by filtration. Thereafter, the residue was distilled under reduced pressure to obtain 1.07 g (yield 64.0%) of a silyl-protected amino group-containing alcohol (iA). As a result of measuring the water content after distillation, the water content was 1 ppm or less.
Silyl-protected amino group-containing alcohol (iA)
Colorless liquid Boiling point: The same result as obtained in [Synthesis Example 1-2] above.
¹ H-NMR (500 MHz, CDCL3): same result as obtained in [Synthesis Example 1-2] above.

[Synthesis Example 3] Synthesis of Compound Represented by Formula (iB) [Synthesis Example 3-1] Synthesis of Compound Represented by Formula (iB-1) 5.00 g of 6-amino-1-hexanol in a 200 ml three-necked flask Then, 15.68 g of triethylamine and 15.00 g of toluene were charged, and then 40.91 g of TESOTf was dropped in a nitrogen atmosphere. Thereafter, the mixture was stirred at 80 ° C. for 25 hours. The reaction solution was transferred to a separatory funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 18.39 g (yield 93.0%) of the silyl protected product (iB-1).
Cyril protector (iB-1)
Colorless liquid Boiling point 180 ° C / 10Pa
¹ H-NMR (500 MHz, CDCL3): δ = 0.63 (18H, q), 0.96 (27H, t), 1.69 (8H, m), 2.83 (2H, m), 3. 40 (2H, t)

[Synthesis Example 3-2] Synthesis of Compound Represented by Formula (iB) Into a 50 ml one-necked flask was charged 5.00 g of silyl protector (iB-1), 5.00 g of methanol, and 29 mg of sodium methoxide, and 18 at 60 ° C. Stir for hours. Thereafter, triethylmethoxysilane was distilled off under reduced pressure, and 5.00 g of methanol was added again and stirred at 60 ° C. The same operation was repeated. After the reaction was completed, the reaction was quenched with sodium hydrogen carbonate, and the solvent was replaced with toluene, and then the salt was removed by filtration. Thereafter, distillation was performed under reduced pressure to obtain 3.35 g (yield: 89.0%) of a silyl-protected amino group-containing alcohol (iB). As a result of measuring the water content after distillation, the water content was 1 ppm or less.
Silyl-protected amino group-containing alcohol (iB)
Colorless liquid Boiling point 108-112 ° C / 10Pa
¹ H-NMR (500 MHz, CDCL3): δ = 0.60 (12H, q), 0.93 (18H, t), 1.68 (8H, m), 2.82 (2H, m), 3. 40 (2H, t)

[Synthesis Example 4] Synthesis of Compound Represented by Formula (IA) [Synthesis Example 4-1] Synthesis of Compound Represented by Formula (IA) Hydrogenation in a 50 mL three-necked flask in a glove box under a nitrogen atmosphere Potassium (manufactured by Kanto Chemical Co., Inc., mineral oil form) was added, and the mineral oil was separated by hexane washing, followed by vacuum drying for about 2 hours to obtain 0.50 g (12.5 mmol) of potassium hydride. 7.71 g of distilled THF was added to the flask with a syringe, and 4.44 g (12.8 mmol) of the compound represented by the formula (iA) was added dropwise at room temperature. After stirring at room temperature for 1 hour, the mixture was stirred at 50 ° C. for 2 hours to obtain 12.40 g (1.02 mmol / g) of a THF solution of the compound represented by the formula (IA). At this time, precipitation of salt and cloudiness were not observed ((IA) mass / THF solution mass = 39.8 wt%). The mass ratio of the polymerization initiator (IA) synthesized by the above reaction and the initiator raw alcohol (iA) is 98: 2 (mol%). The reaction scheme is shown below.

[Synthesis Example 4-2] Alternative Synthesis of Compound Represented by Formula (IA) 2.02 g of naphthalene and 0.68 g of potassium were weighed in a 100 mL three-necked flask in a glove box under a nitrogen atmosphere and vacuum-dried for 1 hour. did. Thereafter, the atmosphere was returned to a nitrogen atmosphere, and 19.65 g of distilled THF was added into the flask with a syringe. Stir for 1 hour to prepare a THF solution of potassium naphthalene (0.71 mmol / g). On the other hand, 1.96 g (5.64 mmol) of the compound represented by the formula (iA) was weighed with a syringe in a 50 mL three-necked flask under a nitrogen atmosphere. 7.85 g of the THF solution of potassium naphthalene prepared above was added dropwise thereto at room temperature. Aging was carried out for 1 hour to obtain 9.77 g (0.58 mmol / g) of a THF solution of a polymerization initiator (IA). At this time, precipitation of salt and white turbidity were not observed ((IA) mass / THF solution mass = 22.3 wt%). The mass ratio of the polymerization initiator (IA) synthesized by the above reaction and the initiator raw alcohol (iA) is 98: 2 (mol%). The reaction scheme is shown below.

Synthesis Example 5 Synthesis of Compound Represented by Formula (I-1A) A stirrer was put into a 500 mL four-necked flask connected with a thermometer, a dropping funnel, and a Dimroth condenser. After keeping the degree of vacuum in the apparatus at 10 Pa or less, the inside of the apparatus was heated using an oil bath and a heat gun to remove moisture in the system. Thereafter, 1.69 g of a THF solution of a compound represented by the formula (IA) prepared from [Synthesis Example 4-1] and 140 g of distilled THF were added into a 2 L four-necked flask under a nitrogen stream. Into the dropping funnel, 20 g of ethylene oxide and 40 g of distilled THF were added, and the resulting solution was dropped little by little into a 500 mL four-necked flask. After confirming that the temperature in the 500 mL four-necked flask was stable, aging was performed at 45 to 50 ° C. for 8 hours. The reaction scheme is shown below.

  After completion of the reaction, the oil bath was removed and the reaction system was cooled to room temperature. A small amount of the obtained reaction solution was sampled, the reaction was stopped with acetic acid, and GPC measurement was performed. As a result, Mw = 8,000 and Mw / Mn = 1.04.

[Synthesis Example 6] Synthesis of Compound Represented by Formula (IIA) [Synthesis Example 6-1] Synthesis of Compound Represented by Formula (IIA) In a reaction solution of the compound represented by Formula (I-1A) Then, 2.41 g of 2-bromoethyl methyl ether and 10.5 mL of a THF solution (1 mol / L) of potassium tert-butoxide were added and stirred while refluxing for 5 hours. After removing the salt in the reaction solution by filtration, the solution was concentrated to 25 wt%, and the concentrated solution was transferred to a dropping funnel. In a 500 mL beaker containing a stirrer, 201 g of hexane was added, and the concentrated solution was dropped therein over 10 minutes, followed by aging for 20 minutes. After filtering the produced white powder, the powder was returned to the original beaker, washed with 99 g of hexane for 20 minutes, and the same washing operation was performed once. The reaction scheme is shown below.

  As a result of vacuum-drying the obtained white powder, 18.6 g of polymer (IIA) was obtained. As a result of GPC measurement, it was Mw = 8,000 and Mw / Mn = 1.05.

[Synthesis Example 6-2] Alternative Synthesis of Compound Represented by Formula (IIA) In a reaction solution of the compound represented by Formula (I-1A), 2.05 g of 2-methoxyethyl p-toluenesulfonate, 0.50 g of potassium tert-butoxide was added, and the mixture was stirred at 40 ° C. for 5 hours. After removing the salt in the reaction solution by filtration, the solution was concentrated to 25 wt%, and the concentrated solution was transferred to a dropping funnel. In a 500 mL beaker containing a stirrer, 200 g of hexane was added, and the concentrated solution was dropped therein over 10 minutes, followed by aging for 10 minutes. After filtering the produced white powder, the powder was returned to the original beaker, washed with 100 g of hexane for 10 minutes, and the same washing operation was performed once. The reaction scheme is shown below.

  As a result of vacuum-drying the obtained white powder, 18.6 g of polymer (IIA) was obtained. As a result of GPC measurement, it was Mw = 8,000 and Mw / Mn = 1.05.

[Synthesis Example 6-3] Alternative Synthesis of Compound Represented by Formula (IIA) A 2 L high-pressure gas reaction vessel was dried by nitrogen purge and synthesized by the method of [Synthesis Example 4-1] in a nitrogen atmosphere. 8.29 g (1.02 mmol / g, 8.46 mmol) of a THF solution of a polymerization initiator (IA) and 885 g of distilled THF were added. After raising the temperature of the reaction vessel to 45 ° C., 100 g of ethylene oxide was continuously injected, and the pressure in the system was adjusted to 0.15 MPa by nitrogen pressurization. When the mixture was stirred at 45 ° C., the pressure in the system gradually decreased, and after 6 hours, the pressure was stabilized at 0.11 MPa and the reaction was terminated. After cooling to 40 ° C., 9.75 g of 2-methoxyethyl-p-toluenesulfonate as an electrophile was dissolved in 97.5 g of THF and pressed into the system, and further 21 ml of a solution of potassium tert-butoxide in THF (1 mol / L). Was diluted with 21 g of THF and pressed into the system. Subsequently, aging was performed for 5 hours while maintaining the temperature at 40 ° C. The precipitated salt was separated by filtration, 17 g of adsorbent KW-2000 was added to the filtrate and stirred for 2 hours, and then the adsorbent was removed by filtration. After concentrating the reaction solution to 400 g, 750 g of hexane and 750 g of ethyl acetate were placed in a 3 L beaker containing a stir bar, and the obtained reaction solution was added dropwise, followed by aging for 10 minutes. After the produced white powder was filtered, the powder was returned to the original beaker, washed with 375 g of hexane and 375 g of ethyl acetate for 10 minutes, and the same washing was repeated once more, and then the obtained white powder was vacuum-dried. As a result, 96 g of polymer (IIA) was obtained. As a result of GPC measurement, it was Mw = 11,400 and Mw / Mn = 1.03. The reaction scheme is shown below.

  As shown in Table 1 below, it can be seen that in Synthesis Example 6-3, polymerization with ethylene oxide proceeds stoichiometrically.

Synthesis Example 7 Synthesis of Compound Represented by Formula (IIIA-a) Synthesis Example 7-1 Synthesis of Compound Represented by Formula (IIIA-a) In a 50 mL three-necked flask, Synthesis Example 6-1 1.0 g of the compound represented by the formula (IIA) obtained in the above, 9.0 g of THF, 1N HClaq. 0.4 ml was added and stirred at 40 ° C. for 4 hours. Thereafter, the reaction was stopped with 0.2 ml of 25 wt% NaOH aqueous solution. After concentrating the reaction solution and distilling off water, 5.7 g of THF was added to adjust the concentration of the polymer solution, and the deposited salt was filtered. 10 g of hexane was placed in a 100 mL beaker containing a stir bar, and the resulting reaction solution was added dropwise, followed by aging for 10 minutes. After filtering the produced white powder, the powder was returned to the original beaker, washed with 5 g of hexane for 10 minutes, and the same washing operation was performed once.

  As a result of vacuum-drying the obtained white powder, 0.7 g of a compound represented by the formula (IIIA-a) was obtained. As a result of GPC measurement, it was Mw = 7,900 and Mw / Mn = 1.05. The reaction scheme is shown below.

  Note that the compound represented by the formula (IIA) may be further deprotected by adding hydrochloric acid without purification after the reaction, in which case the process can be further simplified.

[Synthesis Example 7-2] Alternative Synthesis of Compound Represented by Formula (IIIA-a) In a 1 L three-necked flask, 100 g of the polymer (IIA) obtained in [Synthesis Example 6-3], 400 g of MeOH, and 5.00 g of acetic acid were added. The mixture was added and stirred at 35 ° C. for 3 hours. Thereafter, the reaction was stopped with 24.12 g of a sodium methylate 28% methanol solution. The reaction solution was concentrated and the solvent was replaced with toluene to prepare 450 g of a polymer solution, and the deposited salt was filtered. 100 g of adsorbent KW-2000 was added to the obtained polymer solution and treated at 35 ° C. for 1 hour to remove a trace amount of salt. 1000 g of hexane and 500 g of ethyl acetate were placed in a 3 L beaker containing a stir bar, and the resulting reaction solution was added dropwise, followed by aging for 10 minutes. After filtering the produced white powder, the powder was returned to the original beaker, washed with 600 g of hexane and 300 g of ethyl acetate for 10 minutes, and the same washing operation was performed once.

  As a result of vacuum-drying the obtained white powder, 90 g of polymer (IIIA-a) was obtained. As a result of GPC measurement, it was Mw = 11,000 and Mw / Mn = 1.03. The reaction scheme is shown below.

[Synthesis Example 8] Synthesis of Compound Represented by Formula (IIIB-a) Same as in Synthesis Examples 4 to 7 except that the compound represented by formula (iA) was changed to the compound represented by formula (iB). The compound represented by Formula (IIIB-a) was obtained by the operation of That is, using the compound represented by formula (iB), a polymerization initiator (IB) was synthesized by the same operation as in Synthesis Example 4-1, and using the polymerization initiator, the same as in Synthesis Examples 5-7. The compound represented by Formula (IIIB-a) was obtained by the operation of The same operation as in Synthesis Example 6-1 was performed for Synthesis Example 6 and Synthesis Example 7-1 was performed for Synthesis Example 7. As a result of GPC measurement of the compound represented by the formula (IIIB-a), Mw = 7,900 and Mw / Mn = 1.05. The reaction scheme is shown below.

[Synthesis Example 9] Synthesis of compounds represented by formulas (IIIA-b) to (IIIA-f) Almost the same as Synthesis Examples 4 to 7 except that the ratio of the compound represented by formula (iA) and ethylene oxide was changed. By performing the operation, polymers (IIIA-b) to (IIIA-f) were synthesized. The same operation as in Synthesis Example 4-1 was performed for Synthesis Example 4, Synthesis Example 6-1 for Synthesis Example 6, and Synthesis Example 7-1 for Synthesis Example 7. The analysis results are shown in Table 2.

[Synthesis Example 10] Synthesis of Compounds Represented by Formulas (IIIB-b) to (IIIB-f) Except for changing the ratio of the compound represented by Formula (iB) and ethylene oxide, the same procedure as in Synthesis Example 8 was performed. By performing, the polymers (IIIB-b) to (IIIB-f) were synthesized. The analysis results are shown in Table 3.

[Synthesis Example 11] Synthesis of Formulas (IIIA-g) to (IIIA-l) and (IIIB-g) to (IIIB-l) The substrate 2-bromoethyl methyl ether in [Synthesis Example 6-1] In the same manner as in Synthesis Examples 4 to 7 except that the alkyl group (with a substituent) (R ⁴ ) shown in FIG. The compounds represented by the formulas (IIIB-g) to (IIIB-l) were synthesized by carrying out operations similar to those of Synthesis Example 8 for the compounds represented by g) to (IIIA-l). The same operation as in Synthesis Example 4-1 was performed for Synthesis Example 4, Synthesis Example 6-1 for Synthesis Example 6, and Synthesis Example 7-1 for Synthesis Example 7. The analysis results are shown in Tables 4 and 5.

[Synthesis Example 12] Purification of compound represented by formula (IIIA-a) The inside of a cartridge filled with 50 g of cation exchange resin DIAION PK-208 (manufactured by Mitsubishi Chemical Corporation) was washed with 300 g of 1N hydrochloric acid, followed by ion exchange. The cartridge was washed three times with 300 g of water and then once with 300 g of methanol. A 500 mL two-necked flask was charged with a 5 wt% solution of polymer (IIIA-a) in methanol (polymer content 10 g), and the polymer solution was transferred into the above cartridge using a pump. The methanol solution coming out from the drain port of the cartridge was put into the original 500 mL eggplant flask, and this operation was continued for 2 hours to adsorb the polymer (IIIA-a) to the cation exchange resin. Thereafter, the resin in the cartridge is washed once with 300 g of methanol, and then the polymer (IIIA-a-2) is eluted from the cation exchange resin using 50 g of 7N ammonia solution (methanol solution, manufactured by Kanto Chemical Co., Inc.). It was. The purified polymer after the elution step from the cation exchange resin is shown as (IIIA-a-2).

  Even when the compound represented by the formula (IIA) is used instead of the compound represented by the formula (IIIA-a), the deprotection proceeds with a methanol solution under a cation exchange resin catalyst. Purification could be performed simultaneously and the process could be further simplified.

  The obtained eluent was transferred to a 500 mL eggplant-shaped flask, and ammonia and methanol were distilled off using a rotary evaporator. After concentration under reduced pressure until almost solidified, the solvent was replaced with toluene, and the solid content concentration of the polymer (IIIA-a-2) was adjusted to 25 wt%.

  In a 500 mL beaker containing a stir bar, 100 g of hexane and 50 g of ethyl acetate are mixed, and a 25 wt% solution of the polymer (IIIA-a-2) obtained using a dropping funnel is added dropwise over 10 minutes, followed by stirring for 20 minutes. And matured. After filtering the produced white powder, the powder was returned to the original beaker, washed with a mixed solvent of 50 g of hexane and 25 g of ethyl acetate for 20 minutes, and the same washing operation was performed once.

  As a result of vacuum-drying the obtained white powder, 8.51 g of polymer (IIIA-a-2) was obtained. As a result of GPC measurement, it was Mw = 8,000 and Mw / Mn = 1.05. A compound obtained by concentrating and drying the filtrate obtained by purifying the cation exchange resin when the reaction was carried out in the same manner as in the above example except that the reaction was carried out by mixing a small amount of water during the polymerization. Inside, a by-product due to water mixed during polymerization represented by the following formula (VIIIa) could be confirmed by a very small amount of H-NMR. From the above, even if water is mixed during polymerization, by-products can be removed by the cation exchange resin, and the manufacturing margin can be expanded.

[Comparative Synthesis Example 1] Synthesis of polymer (VIa) Potassium methoxide (manufactured by Kanto Chemical Co., Inc.) was used as a stirring bar and a polymerization initiator in a 500 mL four-necked eggplant flask connected with a thermometer, a dropping funnel and a Dimroth condenser. ) 71 mg (1.01 mmol) was added and the degree of vacuum in the apparatus was kept at 10 Pa or less, and then the inside of the apparatus was heated using an oil bath and a heat gun to remove moisture in the system.

  Thereafter, 40 μL (1.00 mmol) of methanol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 140 g of distilled THF were added into a four-necked flask under a nitrogen stream, and the mixture was stirred at room temperature until potassium methoxide was completely dissolved. The substance amount ratio of the polymerization initiator potassium methoxide synthesized by the above method and methanol which is the starting material alcohol is 50:50 (mol%).

  A mixed solution of ethylene oxide (35 g) and distilled THF (60 g) was charged into the dropping funnel, and the mixture was dropped little by little into the four-necked flask while maintaining the internal temperature at 35 ° C. or lower. After dropping the whole amount, stirring was performed for 80 hours while keeping the internal temperature at 50 ° C. or lower.

  After confirming that there was no change in the conversion rate of ethylene oxide, 0.06 g of acetic acid was added to the flask. After removing ethylene oxide by nitrogen bubbling, the reaction solution was transferred to a 500 mL eggplant-shaped flask and concentrated using a rotary evaporator until a solid was precipitated. 23 g of the polymer crude product was redissolved in 46 g of toluene and transferred to a dropping funnel.

  Into a 500 mL beaker containing a stir bar, 138 g of isopropyl ether was added, and the polymer solution was dropped over 10 minutes using a dropping funnel, followed by aging for 20 minutes. After the produced white powder was filtered, the powder was returned to the original beaker, washed with a mixed solvent of 69 g of isopropyl ether for 20 minutes, and the same washing operation was further performed twice. The reaction scheme is shown below.

  As a result of vacuum-drying the obtained white powder, 18.54 g of a comparative polymer (VIa) was obtained. As a result of GPC measurement, it was Mw = 7,200 and Mw / Mn = 1.16.

[Comparative Synthesis Example 2] Synthesis of polymer (IXa) In a 300 ml four-necked flask, 10.00 g of polymer (VIa), 29.5 g of THF, 0.56 g of 10 wt% potassium hydroxide aqueous solution, 0.5 g of H ₂ O, 1.06 g of acrylonitrile. And stirred at room temperature for 6 hours. After completion of the reaction, 1.45 g of an alkali adsorbent “Tomita AD700NS” (trade name, synthetic aluminum silicate, manufactured by Tomita Pharmaceutical Co., Ltd.) was added, and the reaction was performed for 2 hours. After filtering the alkali adsorbent, the filtrate was transferred to a 300 mL eggplant flask, and the solvent was replaced with toluene, and the solution was concentrated until the solid content concentration of the comparative polymer (IXa) was 25 wt%.

  In a 500 mL beaker containing a stir bar, 100 g of hexane and 50 g of ethyl acetate were mixed, and the concentrated solution obtained using a dropping funnel was added dropwise over 10 minutes, followed by aging for 20 minutes. After filtering the produced white powder, the powder was returned to the original beaker, washed with a mixed solvent of 50 g of hexane and 25 g of ethyl acetate for 20 minutes, and the same washing operation was performed once. The reaction scheme is shown below.

  As a result of vacuum-drying the obtained white powder, 9.12 g of a comparative polymer (IXa) was obtained. As a result of GPC measurement, it was Mw = 7,300 and Mw / Mn = 1.15.

[Comparative Synthesis Example 3] Synthesis of polymer (IIIc) 5.0 g of polymer (IXa), 5.0 g of Raney cobalt catalyst R-400 (manufactured by Nikko Rica Co., Ltd.), 45 in a 500 mL hydrogen reduction autoclave, 45 0.0 g of methanol and 3.0 mL of a 1N methanol solution of ammonia (manufactured by Aldrich) were added at room temperature. Thereafter, hydrogen gas (pressure = 10 kg / cm ² ) was sealed, heated until the internal temperature reached 120 ° C., and reacted for 6 hours as it was. After cooling to room temperature, the pressure was returned to atmospheric pressure, and then ammonia in the system was removed while blowing nitrogen. After removing the Raney cobalt catalyst by filtration, the filtrate was transferred to a 100 mL eggplant-shaped flask, and ammonia and methanol were distilled off using a rotary evaporator. After concentration under reduced pressure until dryness, 4.5 g of a mixture of polymer (IIIc) and the following general formulas (IVc) to (VIc) was obtained. As a result of GPC measurement, it was Mw = 7,300 and Mw / Mn = 1.25. The reaction scheme and by-products are described below.

[Analysis of Impurity Content of Products Obtained in Synthesis Examples 7-1, 8, 12 and Comparative Synthesis Example 3]
Impurity content analysis was performed on the product obtained in [Synthesis Example 7-1], [Synthesis Example 8] and [Synthesis Example 12] and the product obtained in [Comparative Synthesis Example 3]. The results are shown in Table 6 below.
The compound represented by mPEG in Table 6 is a compound corresponding to the general formula (VIc) in [Comparative Synthesis Example 3], and is a compound in which acrylonitrile is β-eliminated from a polymer having a cyanoethyl group at the terminal. The composition ratio of mPEG was calculated by H-NMR measurement. First, 10 mg of each of the products obtained in [Synthesis Example 7-1], [Synthesis Example 8], [Synthesis Example 12], and [Comparative Synthesis Example 3] was weighed and dissolved in 0.75 ml of CDCl3. , 50 mg of trifluoroacetic anhydride was added and left for 1 day. A proton derived from an ester α-position methylene of a compound represented by the following general formula (VI-1) produced by this treatment and a proton derived from an amide α-position methylene of a compound represented by the following general formula (III-1) The composition ratio of mPEG was calculated from the ratio.
In the table, the compound expressed as secondary amine or tertiary amine is a compound corresponding to the general formulas (IVc) and (Vc) in [Comparative Polymer Synthesis Example 3]. The amount of contamination was measured by GPC, and calculated from the area percentage of the polymer corresponding to 2 times or 3 times the molecular weight.
From these results, in the comparative polymer (IIIc), β-elimination of acrylonitrile by hydrogen reduction and formation of secondary and tertiary amines were observed. However, the polymers of Examples (IIIA-a), (IIIB-a), (IIIA) In -a-2), these by-products were not observed.

[Metal analysis of products obtained in Synthesis Examples 7-1, 8, and 12 and Comparative Synthesis Example 3]
High frequency inductively coupled plasma mass spectrometer (ICP-MS) of the product obtained in [Synthesis Example 7-1], [Synthesis Example 8] and [Synthesis Example 12] and the product obtained in [Comparative Synthesis Example 3] , Agilent Technologies 7500cs). The measurement was performed by a standard addition method using a sample obtained by diluting each product 100 times with ultrapure water. The analysis results (in terms of solid content) are shown in Table 7 (unit: ppb).
As a result of metal analysis, the comparative polymer (IIIc) contains heavy metal used during the reduction, whereas [Synthesis Example 7-1], [Synthesis Example 8], and [Synthesis Example 12] do not use a heavy metal catalyst. Therefore, it can be seen that the example polymers (IIIA-a), (IIIB-a), and (IIIA-a-2) do not contain heavy metals.

[Synthesis of polymerization initiator and comparative polymerization initiator, and comparison of solubility in polymerization solvent]
The results of synthesizing polymerization initiators other than those used above (initiators 2-9, 11, 12, and comparative initiators 1-8) are shown below. In the following, “initiator 1” is a polymerization initiator represented by formula (IA) synthesized using a compound represented by formula (iA) in [Synthesis Example 4-1]. Agent 10 ”is a polymerization initiator (IB) synthesized using the compound represented by formula (iB) in [Synthesis Example 8].

[Synthesis of Initiator 2]
Initiator 2 was synthesized in the same manner as described in [Synthesis Example 2-3] and [Synthesis Example 4-1] except that the ethylene glycol used in [Synthesis Example 2-3] was changed to diethylene glycol. .

[Synthesis of Initiator 3]
The method described in [Synthesis Example 2-4] and [Synthesis Example 4-1] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiC): In the same manner, initiator 3 was synthesized.

[Synthesis of Initiator 4]
Initiator 4 was synthesized in the same manner as described in [Synthesis of Initiator 3] except that ethylene glycol used in [Synthesis Example 2-4] was changed to diethylene glycol.

[Synthesis of Initiator 5]
[Synthesis Example 2-4] and [Synthesis Example] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiD) and ethylene glycol was changed to triethylene glycol. Initiator 5 was synthesized in the same manner as described in [4-1].

[Synthesis of Initiator 6]
The method described in [Synthesis Example 2-4] and [Synthesis Example 4-1] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiE). Initiator 6 was synthesized in the same manner.

上記求電子剤（ｉｉＥ）及び開始剤６中、ＴＢＳはｔｅｒｔ−ブチルジメチルシリルのことである。

In the electrophile (iiE) and initiator 6, TBS is tert-butyldimethylsilyl.

[Synthesis of initiator 7]
The method described in [Synthesis Example 2-4] and [Synthesis Example 4-1] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiF): In the same manner, initiator 7 was synthesized.

[Synthesis of Initiator 8]
The method described in [Synthesis Example 2-4] and [Synthesis Example 4-1] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiG): In the same manner, initiator 8 was synthesized.

[Synthesis of Initiator 9]
The method described in [Synthesis Example 2-4] and [Synthesis Example 4-1] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiH). Initiator 9 was synthesized in the same manner.

[Synthesis of Initiator 11]
To a 300 ml three-necked flask, 15.7 g of 6-amino-1-hexanol, 91.0 g of THF, and 46.3 g of potassium carbonate were charged, and then 28.4 ml of allyl bromide was added dropwise while cooling with ice in a nitrogen atmosphere. Then, it stirred at normal temperature for 1 hour. The reaction solution was filtered and distilled under reduced pressure to obtain 13.2 g (yield 50.0%) of the starting alcohol 11 (iC). Subsequently, an initiator 11 was synthesized in the same manner as described in [Synthesis Example 4-1].

[Synthesis of Initiator 12]
Initiator 12 was synthesized in the same manner as [Synthesis of Initiator 11] except that allyl bromide was changed to 1,2-bis (chlorodimethylsilyl) ethane.

[Synthesis of Comparative Initiator 1]
Using the silyl-protected amino group-containing alcohol (iiA-2) used in [Synthesis Example 2-1] as a raw material, Comparative Initiator 1 was synthesized in the same manner as described in [Synthesis Example 4-1]. .

[Synthesis of Comparative Initiator 2]
Comparative initiator 2 was synthesized in the same manner as described in [Synthesis of Comparative Initiator 1] except that the protecting group triethylsilyl was changed to trimethylsilyl (TMS).

上記比較開始剤２中のＴＭＳはトリメチルシリルのことである。

TMS in the comparative initiator 2 is trimethylsilyl.

[Synthesis of Comparative Initiator 3]
Comparative Initiator 3 in the same manner as described in [Synthesis of Initiator 11] except that 6-amino-1-hexanol used in [Synthesis of Initiator 11] was changed to 3-amino-1-propanol. Was synthesized.

[Synthesis of Comparative Initiator 4]
A comparative initiator 4 was synthesized in the same manner as described in [Synthesis Example 4-1] except that the following (iD) was used as a raw material alcohol instead of the compound represented by the formula (iA).

[Synthesis of Comparative Initiator 5]
Comparative initiator 5 was synthesized in the same manner as described in [Synthesis Example 4-1] except that the following (iE) was used as the raw material alcohol instead of the compound represented by formula (iA).

[Synthesis of Comparative Initiator 6]
Comparative initiator 6 was prepared in the same manner as described in [Synthesis of initiator 12] except that 6-amino-1-hexanol used in [Synthesis of initiator 12] was changed to 3-amino-1-propanol. Synthesized.

[Synthesis of Comparative Initiator 7]
Comparative initiator 7 was synthesized in the same manner as described in [Synthesis of comparative initiator 3] except that allyl bromide used in [Synthesis of comparative initiator 3] was changed to benzyl bromide.

[Synthesis of Comparative Initiator 8]
A compound represented by the following formula (iF) was synthesized by the reaction shown in Scheme 1 below. Comparative initiator 8 was prepared in the same manner as described in [Synthesis Example 4-1] except that the compound represented by formula (iF) was used instead of the compound represented by formula (iA). Synthesized.

1) Synthesis of Boc Protection (iF-1) 5.11 g of 3-amino-1-propanol, 7.21 g of triethylamine, 55.43 g of methanol, di-tert-butyl dicarbonate (hereinafter referred to as Boc2O) in a 200 ml three-neck flask 61 g was charged and stirred at room temperature for 14 hours under a nitrogen atmosphere. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The obtained ethyl acetate solution was concentrated under reduced pressure to obtain 10.73 g (crude yield 90%) of Boc protection (iF-1).

2) Synthesis of TBS protection (iF-2) 10.61 g of Boc protection (iF-1) and 241.80 g of THF were added to a 500 ml three-necked flask, and 9.26 g of imidazole and 15.38 g of TBSCl were added while cooling with ice in a nitrogen atmosphere. Added. After returning to room temperature and stirring for 22 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with isopropyl ether. The resulting isopropyl ether solution was concentrated under reduced pressure to obtain 18.24 g (crude yield 93%) of TBS protection (iF-2).

3) Synthesis of Boc protection (iF-3) 10.01 g of TBS protection (iF-2) and 155.58 g of dehydrated THF were added to a 500 ml two-necked flask, and n-butyllithium / hexane solution was cooled with ice in a nitrogen atmosphere. (2.69M) 16.68 mL was added dropwise. After stirring at the same temperature for 30 minutes, 40.87 g of Boc 2 O / THF solution (26 wt%) was added dropwise, and the mixture was returned to room temperature and stirred for 2.5 hours. The reaction solution was diluted with isopropyl ether and washed with a saturated aqueous ammonium chloride solution, and then the resulting solution was concentrated under reduced pressure to obtain 14.77 g (crude yield 100%) of TBS protection (iF-3).

4) Synthesis of alcohol (iF) In a 500 ml three-necked flask, 14.77 g of TBS protection (iF-3) and 110.59 g of THF were charged, and TBAF (tetra-n-butylammonium fluoride) / THF was stirred at room temperature in a nitrogen atmosphere. 39.5 mL of solution (1M) was added. After stirring at the same temperature for 5 hours, the mixture was diluted with isopropyl ether and washed with ultrapure water. The obtained isopropyl ether solution was concentrated under reduced pressure to obtain 10.22 g of alcohol (iF) (crude yield: 98%).

上記スキーム中Ｂｏｃはｔｅｒｔ−ブトキシカルボニルのことである。

In the above scheme, Boc is tert-butoxycarbonyl.

  The structures of the various polymerization initiators synthesized above (initiators 1 to 12 and comparative initiators 1 to 8) are summarized below.

Next, the solubility results of the initiators 1 to 12 and the comparative initiators 1 to 8 in the polymerization solvent are shown. The table below shows the results of dissolving the initiators 1 to 12 synthesized above and the THFs of the comparative initiators 1 to 8 under reduced pressure, taking out the polymerization initiator, and dissolving each in a polymerization solvent at a concentration of 20 wt%. “O” indicates that no turbidity is observed by visual inspection, “X” indicates that turbidity is observed or does not dissolve at all, or decomposes at the stage of alkoxide formation, and “−” indicates that the undetermined one is not. .

  When the synthesis of comparative initiators 1, 2, 5, and 6 was examined, the change of the protecting group in the molecule progressed, but in initiators 1, 2, 6, 7, 10, and 12 that extended the chain length, The initiator was present stably and dissolved in the solvent. On the other hand, the compounds that were not dissolved in the solvent by the comparative initiators 3, 4, 7, and 8 were also dissolved in the solvent by the initiators 3, 4, 5, 8, 9, and 11 whose chain length was extended.

  As a result of the above Examples and Comparative Examples, in Synthesis Example 5 and Comparative Synthesis Example 1, the latter requires polymerization time of 80 hours due to the presence of the initiator raw alcohol, whereas the former is the initiator raw alcohol. It can be seen that the polymerization reaction is completed within 8 hours by using a polymerization initiator that is soluble in THF even in a state in which the remaining amount of is low. That is, the polymerization of alkylene oxide under mild conditions was realized by the method of the present invention. Further, in Synthesis Example 6, the reaction solution of Synthesis Example 5 was used directly in the next step reaction without post-treatment, thereby greatly simplifying the process. Furthermore, in Synthesis Example 12, it became possible to purify the polymer by a simple method without using lyophilization in the final step by using an organic solvent for the purification of the resin using the ion exchange resin.

  In Synthesis Examples 5 to 8 and Comparative Synthesis Examples 1 to 3, the latter requires a hydrogenation reaction using a heavy metal as a catalyst for the reduction of the cyano group, whereas in the former, the target polymer is obtained simply by deprotecting the protected amino group. Can be synthesized. In comparative polymer (IIIc), β-elimination of acrylonitrile and formation of secondary and tertiary amines occurred by hydrogen reduction. Examples (IIIA-a), (IIIB-a), (IIIA-a-2) Then, no generation was observed (Table 6). Further, in Synthesis Examples 7-1, 8, and 12 and Comparative Synthesis Example 3, as a result of metal analysis, heavy metals used during the reduction were mixed in the comparative polymer, whereas in Synthesis Examples 7-1, 8, and 12, heavy metal catalysts were used. Since no is used, it can be seen that heavy metals are essentially not mixed. Moreover, the amount of potassium metal contamination could be reduced by purification with a strongly acidic cation exchange resin (Table 7). As a result, according to the present invention, the synthesis of an amino group-containing narrowly dispersed polyalkylene glycol derivative free from heavy metal contamination that may adversely affect pharmaceuticals was achieved. In addition, by synthesizing a novel protected amino group-containing alcohol and using it as a raw material, it can be applied to various polymer syntheses. By using the above-mentioned novel polymerization initiator and further purifying with a cation exchange resin as necessary, it is possible to remove the diol polymer that has been difficult to separate due to water contamination, and contains amino groups with high purity. A narrowly dispersed polyalkylene glycol derivative can be obtained, and the manufacturing margin can be expanded.

  The polymer compound produced by using the method of the present invention can be widely used as a starting material when synthesizing a block copolymer used in applications such as pharmaceuticals and cosmetics including the field of drug delivery systems. . In addition, novel metal salts of protected amino group-containing alcohols can be applied to various polymer synthesis.

Claims (26)

The manufacturing method of the polyalkylene glycol derivative which has an amino group at the terminal at least including the process of making the polymerization initiator represented by the following general formula (I) and alkylene oxide react.

(In the general formula (I), R _A ^1a and R _A ^1b each independently represent an amino group protecting group, or one of them represents a hydrogen atom and the other represents an amino group protecting group, or R _A ^1a And R _A ^1b represents a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbon atoms, or branched or cyclic having 3 to 6 carbon atoms And R _A ³ is a single bond, a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent group having 3 to 20 carbon atoms. Wherein the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a heteroatom, the carbon atoms of R _A ² and R _A ³ and The total number of heteroatoms is 4 or more, and M represents an alkali metal) A process for producing a polyalkylene glycol derivative having an amino group at the terminal, comprising steps a) to c):

(In the general formulas (I) to (III),
R _A ^1a and R _A ^1b each independently represent an amino protecting group, one represents a hydrogen atom, the other represents an amino protecting group, or R _A ^1a and R _A ^1b are bonded to each other. A cyclic protecting group that forms a ring with the nitrogen atom of the amino group,
R _A ² is a straight chain having 1 to 6 carbon atoms, or a branched or cyclic divalent hydrocarbon group having 3 to 6 carbon atoms,
R _A ³ is a single bond or a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent hydrocarbon group having 3 to 20 carbon atoms,
Here, the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a hetero atom, the total number of carbon atoms and hetero atoms of R _A ² and R _A ³ is 4 or more. And
R _A ⁴ is a hydrogen atom or an optionally substituted linear, branched or cyclic hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group may contain a hetero atom,
R _A ⁵ is an alkylene group having 2 to 8 carbon atoms,
M represents an alkali metal,
n is an integer of 1 to 450)
Step a) A step of obtaining a compound represented by the following general formula (I-1) by reacting a polymerization initiator represented by the general formula (I) with an alkylene oxide in a polymerization solvent.

(In the general formula (I-1), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ are as defined for the general formula (II), and the general formula (II ) R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ , M represents an alkali metal, is the same as M in the general formula (I), and r is 1 Represents an integer of ~ 445);
Step b) A compound represented by the general formula (II) is obtained by reacting a compound represented by the general formula (I-1) with a compound represented by the following general formula (I-2). Process

(In the general formula (I-2), R _A ⁴ and R _A ⁵ are as defined for the general formulas (II) and (III), and R _A ^{4 in the} general formulas (II) and (III)). And R _A ⁵ , k represents an integer of 0 to 5, L represents a leaving group); and step c) the compound represented by the general formula (II) is deprotected, A step of obtaining a compound represented by the formula (III). In the general formulas (I) to (III), R _A ^1a and R _A ^1b are protective groups that can be deprotected without using a heavy metal catalyst, and in the step c), the general formula (II) The method of Claim 2 which deprotects the compound represented by these, without using a heavy metal catalyst. Before the step a), the method further includes a pre-process for synthesizing the polymerization initiator represented by the general formula (I), and the pre-process includes a compound represented by the following general formula (i); ^{_{M, M + H -, R}} X - M +, [R Y] · - represents an alkali metal or an alkali metal compound selected from ^{M +} (wherein, M is an alkali metal, - ^{M +,} and _R Z ^O R _X represents an optionally substituted alkyl group having 1 to 20 carbon atoms, R _Y represents an optionally substituted aromatic compound, and R _Z represents 1 to 6 carbon atoms. The method according to claim 2, comprising at least a step of obtaining a polymerization initiator represented by the general formula (I) by reacting with an alkyl group.

(In the general formula (i), R _A ^1a , R _A ^1b , R _A ² and R _A ³ are as defined for the general formula (I), and R _A in the general formula (I) ^1a , R _A ^1b , R _A ² and R _A ³ are the same) The polymerization initiator represented by the general formula (I) used in the step a) is a polymerization initiator represented by the following general formula (1) and / or (2), and in the step c) The method according to any one of claims 2 to 4, wherein the obtained compound represented by the general formula (III) is a compound represented by the following general formula (3) and / or (4).

(In the general formulas (1) and (2), each R ¹ is independently a linear chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon group having 3 to 6 carbon atoms, Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring together with the silicon atoms to which these are bonded, and R ² is a straight chain having 1 to 6 carbon atoms, or a branched structure having 3 to 6 carbon atoms or A cyclic divalent hydrocarbon group, R ³ is a linear divalent hydrocarbon group having 4 to 6 carbon atoms, R ⁵ is an alkylene group having 2 to 8 carbon atoms, and M is an alkali Represents a metal, m represents an integer of 1 to 3)

(In the general formulas (3) and (4), R ² , R ³ , R ⁵ , and m are as defined for the general formulas (1) and (2), and the general formula (1) and (2) is the same as R ² , R ³ , R ⁵ and m in (2), and R ⁴ is a hydrogen atom or an optionally substituted linear, branched or cyclic carbon having 1 to 12 carbon atoms. A hydrocarbon group, and the hydrocarbon group may contain a hetero atom, and n is an integer of 1 to 450) The method according to claim 5, wherein the compound represented by the general formula (i) used in the previous step is a compound represented by the following general formula (6) and / or (7).

(In the above general formulas (6) and (7), R ¹ , R ² , R ³ , R ⁵ , and m are as defined for the general formulas (1) and (2), (Same as R ¹ , R ² , R ³ , R ⁵ , and m in (1) and (2))   In the preceding step, after synthesizing the polymerization initiator represented by the general formula (I) from the compound represented by the general formula (i), the polymerization initiator represented by the general formula (I) and the general formula ( The compound represented by the general formula (i) and an alkali metal or an alkali metal compound are reacted so that a substance amount ratio with the compound represented by i) is 100: 0 to 80:20. The method of any one of -6.   In the preceding step, by synthesizing the polymerization initiator represented by the general formula (I) from the compound represented by the general formula (i), the compound represented by the general formula (i) is distilled off under reduced pressure. The substance amount ratio between the polymerization initiator represented by the general formula (I) and the compound represented by the general formula (i) is set to 100: 0 to 98: 2, 8. The method described in 1.   The method according to any one of claims 4 to 8, wherein the previous step further comprises a step of synthesizing the compound represented by the general formula (i).   The method according to any one of claims 4 to 9, wherein the step a) comprises dissolving the reaction product obtained in the previous step in a polymerization solvent.   The method according to any one of claims 2 to 10, wherein in the step a), the polymerization initiator represented by the general formula (I) is dissolved in the polymerization solvent without cloudiness or salt precipitation.   The method according to any one of claims 2 to 11, wherein the polymerization solvent used in the step a) is a simple solvent or a mixed solvent selected from the group consisting of cyclic ether compounds having 4 to 10 carbon atoms. . The method according to any one of claims 2 to 12, wherein, in the general formulas (I) to (III), R _A ³ is represented by the following general formula (VII).
-(OR _A ⁵ ) _P- (VII)
(In General Formula (VII), R _A ⁵ is as defined for General Formulas (II) and (III), and is the same as R _A ^{5 in} General Formulas (II) and (III); p is an integer of 1 to 10)   The method according to any one of claims 2 to 13, wherein the reaction in the step a) is carried out at a reaction temperature of 30 to 80C. The compound represented by the following general formula (IV) and the compound represented by the following general formula (V) in the reaction product containing the compound represented by the above general formula (III) obtained in the step c) The area ratio measured by gel permeation chromatography was 3% or less, and the composition ratio measured by proton nuclear magnetic resonance of the compound represented by the following general formula (VI) in the reaction product The method according to any one of claims 2 to 14, wherein the content is 2 mol% or less.

(In the general formulas (IV) to (VI), R _A ² , R _A ³ , R _A ⁴ , R _A ⁵ , and n are as defined for the general formulas (II) and (III), (It is the same as R _A ² , R _A ³ , R _A ⁴ , R _A ⁵ and n in the general formulas (II) and (III))   The heavy metal impurity content in the reaction product containing the compound represented by the general formula (III) obtained in the step c) is 100 ppb or less, and the heavy metal impurity is Co, Ni, Pd, Pt, Rh, The method according to any one of claims 2 to 15, which is at least one selected from the group consisting of Ru, Cu, and Cr.   After the step c) obtains the compound represented by the general formula (III), the reaction product containing the compound represented by the general formula (III) is reacted with a basic compound to form a salt. 17. The method of any one of claims 2-16, further comprising allowing the resulting salt to then be removed by filtration.   After the step c) obtains the compound represented by the general formula (III), the reaction product containing the compound represented by the general formula (III) is reacted with a basic compound to form a salt. 17. The method of any one of claims 2 to 16, further comprising allowing the resulting salt to then be removed using an adsorbent.   The reaction product containing the compound represented by the general formula (III) obtained in the step c) is reacted with a strongly acidic cation exchange resin, and the strongly acidic cation exchange resin is reacted with water or a carbon number of 1 to 5. And a post-treatment step of separating and purifying the compound represented by the general formula (III) by reacting the strongly acidic cation exchange resin with a basic compound after washing with a monohydric alcohol. The method according to any one of claims 2 to 18. The method according to claim 19, wherein the compound represented by the following general formula (VIII) is removed from the strongly acidic cation exchange resin in the washing in the post-treatment step.
R _A ⁴ O (R _A ⁵ O) _p R _A ⁴ (VIII)
(In the general formula (VIII), R _A ⁴ and R _A ⁵ are as defined for the general formulas (II) and (III), and R _A ⁴ and R in the general formulas (II) and (III)). is identical to _a ^5, p is an integer of 1 to 890) A metal salt of a protected amino group-containing alcohol compound represented by the following general formula (I).

(In the general formula (I), R _A ^1a and R _A ^1b each independently represent an amino group protecting group, or one of them represents a hydrogen atom and the other represents an amino group protecting group, or R _A ^1a And R _A ^1b represents a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbon atoms, or branched or cyclic having 3 to 6 carbon atoms And R _A ³ is a single bond, a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent group having 3 to 20 carbon atoms. Wherein the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a heteroatom, the carbon atoms of R _A ² and R _A ³ and The total number of heteroatoms is 4 or more, and M represents an alkali metal) Following general formula (6) or (7) a silyl-protected amino group-containing alcohol compound represented by the.

(In the general formulas (6) and (7), each R ¹ is independently a linear chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon group having 3 to 6 carbon atoms, Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring together with the silicon atom to which these are bonded, and R ² may be formed from a methyl group, an n-propyl group, an n-pentyl group, or an n-hexyl group, A group in which one atom is eliminated , or a branched or cyclic divalent hydrocarbon group having 3 to 6 carbon atoms, and R ³ is a linear divalent hydrocarbon group having 4 to 6 carbon atoms. And R ⁵ is an alkylene group having 2 to 8 carbon atoms, and m represents an integer of 1 to 3). The metal salt of a protected amino group-containing alcohol compound according to claim 21 , which is a metal salt of a silyl-protected amino group-containing alcohol compound represented by the following general formula (1) or (2).

(In the general formulas (1) and (2), each R ¹ is independently a linear chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon group having 3 to 6 carbon atoms, Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring together with the silicon atoms to which these are bonded, and R ² is a straight chain having 1 to 6 carbon atoms, or a branched structure having 3 to 6 carbon atoms or A cyclic divalent hydrocarbon group, R ³ is a linear divalent hydrocarbon group having 4 to 6 carbon atoms, R ⁵ is an alkylene group having 2 to 8 carbon atoms, and M is an alkali Represents a metal, m represents an integer of 1 to 3) A method for producing a silyl-protected amino group-containing alcohol compound represented by the general formula (6) or (7) according to claim 22 , wherein the trisilyl-protected compound is represented by the following general formula (8) or (9) A method for producing a silyl-protected amino group-containing alcohol compound, which comprises a step of treating with a base.

(In the general formulas (8) and (9), R ¹ , R ² , R ³ , R ⁵ , and m are as defined for the general formulas (6) and (7)). 6) and (7) are the same as R ¹ , R ² , R ³ , R ⁵ , and m) A process for producing a polyalkylene glycol derivative having a protected amino group at the terminal represented by the following general formula (II), comprising the steps a) and b):

(In the general formulas (I) and (II),
R _A ^1a and R _A ^1b each independently represent an amino protecting group, one represents a hydrogen atom, the other represents an amino protecting group, or R _A ^1a and R _A ^1b are bonded to each other. A cyclic protecting group that forms a ring with the nitrogen atom of the amino group,
R _A ² is a straight chain having 1 to 6 carbon atoms, or a branched or cyclic divalent hydrocarbon group having 3 to 6 carbon atoms,
R _A ³ is a single bond or a straight chain having 1 to 20 carbon atoms which may contain a hetero atom, or a branched or cyclic divalent hydrocarbon group having 3 to 20 carbon atoms,
Here, the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a hetero atom, the total number of carbon atoms and hetero atoms of R _A ² and R _A ³ is 4 or more. And
R _A ⁴ is a hydrogen atom or an optionally substituted linear, branched or cyclic hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group may contain a hetero atom,
R _A ⁵ is an alkylene group having 2 to 8 carbon atoms,
M represents an alkali metal,
n is an integer of 1 to 450)
Step a) A step of obtaining a compound represented by the following general formula (I-1) by reacting a polymerization initiator represented by the general formula (I) with an alkylene oxide in a polymerization solvent.

(In the general formula (I-1), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ are as defined for the general formula (II), and the general formula (II ) R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ , M represents an alkali metal, is the same as M in the general formula (I), and r is 1 And step b) by reacting the compound represented by the general formula (I-1) with the compound represented by the following general formula (I-2), Step of obtaining a compound represented by II)

(In General Formula (I-2), R _A ⁴ and R _A ⁵ are as defined for General Formula (II) and are the same as R _A ⁴ and R _A ^{5 in} General Formula (II). , K represents an integer of 0 to 5, and L represents a leaving group). A silyl-protected amino group-containing polyalkylene glycol compound derivative represented by the following general formula (II-1) or (II-2).

(In the general formulas (II-1) and (II-2), each R ¹ is independently a linear chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon having 3 to 6 carbon atoms. R ¹ may be bonded to each other to form a 3- to 6-membered ring together with the silicon atoms to which they are bonded, and R ² may be a methyl group, an n-propyl group, an n-pentyl group, or an n-hexyl group. A group in which one hydrogen atom is removed from the group , or a branched or cyclic divalent hydrocarbon group having ³ to 6 carbon atoms, and R ³ is a linear divalent hydrocarbon group having 4 to 6 carbon atoms. A hydrocarbon group, R ⁴ is a hydrogen atom or an optionally substituted linear, branched or cyclic hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group is a hetero atom; may also comprise, ^{R 5} is an alkylene group having 2 to 8 carbon atoms, m represents an integer of 1 to 3, n is 450 of an integer)